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Purpose Opportunities exist to meaningfully reduce suboptimal prescription opioid use among older adults. Deprescribing is one possible approach to reducing suboptimal use. Appropriate interventions should outline how to carefully taper opioids, closely monitor adverse events, substitute viable alternative and affordable nonopioid pain treatments, and initiate medications for opioid use disorder to properly manage use disorders, as needed. We sought to document and understand provider perceptions to begin developing effective and safe opioid deprescribing interventions. Methods We conducted 3 semistructured focus groups that covered topics such as participant perspectives on opioid deprescribing in older adults, how to design an ideal intervention, and how to identify potential barriers or facilitators in implementing an intervention. Focus group transcripts were double coded and qualitatively analyzed to identify overarching themes. Results Healthcare providers (n = 17), including physicians, pharmacists, nurses, social workers, and administrative staff, participated in 3 focus groups. We identified 4 key themes: (1) involve pharmacists in deprescribing and empower them as leaders of an opioid deprescribing service; (2) ensure tight integration and close collaboration throughout the deprescribing process from the inpatient to outpatient settings; (3) more expansive inclusion criteria than age alone; and (4) provision of access to alternative pharmacological and nonpharmacological pain management modalities to patients. Conclusion Our findings, which highlight various healthcare provider beliefs about opioid deprescribing interventions, are expected to serve as a framework for other organizations to develop and implement interventions. Future studies should incorporate patients’ and family caregivers’ perspectives.

OBJECTIVE To determine whether premedical programming can address the interest level and perception of barriers to women in orthopaedics held by female high school and medical students. DESIGN A thirteen-question paper-based survey was distributed among the high school and medical school participants prior to the January 2020 Perry Outreach Program and Medical Student Outreach Program. After a day of participation in mock procedures and speaker sessions, participants subsequently completed another survey of seven-questions. SETTING The Perry Outreach Program and Medical Student Outreach Program were conducted at the University of Alabama at Birmingham campus. PARTICIPANTS Participants consisted of high school and medical school women hailing from the Birmingham metropolitan area, who had signed up for the Perry programs via email, outreach to local high schools, and social media interest pages. Participant sampling was stratified by race and level of education (high school vs. medical school). RESULTS A total of 36 women, 18 high school and 18 medical school, attended the Perry Initiative events and responded to the pre-event and post-event surveys. Before the Perry Initiative programs, all participants felt women faced more barriers than men in pursuing a career in orthopaedics. Participation in the Perry Initiative event increased average interest in orthopaedics by 28% among high school and 11% among medical school students. CONCLUSIONS Prior to the Perry Initiative, 31% percent of the total attendees reported knowing a female orthopaedist. The Perry Initiative improved perceptions of both high school and medical students regarding the ability of women to have a work/life balance, family life, and children during orthopaedics residency. Medical student participation in the events led to a decreased belief in barriers regarding schedule, family life, perceptions of an orthopaedic surgeon, and perceptions of peers within healthcare setting.

Clinicians and medical researchers increasingly turn to nonformal online platforms to promote research. Altmetric Attention Score (AAS) is a quantitative measurement of online influence of research in real time. The objective of this study is to determine if AAS correlates with traditional bibliometrics in the orthopaedic literature.From the 15 orthopaedic journals with the highest impact factor, the 10 most cited articles from each journal were reviewed for 2014 -2017. For each article, AAS was collected using the Altmetric Bookmarklet application and citation count from SCOPUS. Journal impact factor was recorded using Journal Citation Reports. Statistical analysis included Pearson's and Spearman's correlation coefficients.A total of 600 articles were analyzed. A significant positive correlation was found between citation count and AAS for 2014 (r = 0.3188, p0.0001), and no correlation for 2015 (r = 0.1504, P = 0.0653), 2016 (r = 0.0087, P = 0.9157), and 2017 (r = 0.0061, P = 0.9408). There was no significant correlation between impact factor and AAS in 2014 (r = 0.4312, P = 0.1085), 2015 (r = 0.3850, P = 0.1565), 2016 (r = 0.1460, P = 0.6035) and 2017 (r = 0.0451 P = 0.8732).AAS and traditional bibliometrics are currently not strongly correlated in orthopaedic literature. Citations take years to accumulate and AAS represents immediate influence of an article. An amalgamation of traditional bibliometrics and AAS may prove useful in determining the short- and long-term impact and influence of publications in orthopaedics.

The nebular spectra of Type Ia supernovae ($\gtrapprox$ 100 days after explosion) consist mainly of emission lines from singly- and doubly-ionised Fe-group nuclei. However, theoretical models for many scenarios predict that non-thermal ionisation leads to multiply-ionised species whose recombination photons ionise and deplete Fe$^{+}$ , resulting in negligible [Fe II] emission. We investigate a method to determine the collisional excitation conditions from [Fe II] line ratios independently from the ionisation state and find that it cannot be applied to highly-ionised models due to the influence of recombination cascades on Fe$^{+}$ level populations. When the ionisation state is artificially lowered, the line ratios (and excitation conditions) are too similar to distinguish between explosion scenarios. We investigate changes to the treatment of non-thermal energy deposition as a way to reconcile over-ionised theoretical models with observations and find that a simple work function approximation provides closer agreement with the data for sub-Mch models than a detailed Spencer-Fano treatment with widely-used cross section data. To quantify the magnitude of additional heating processes that would be required to sufficiently reduce ionisation from fast leptons, we artificially boost the rate of energy loss to free electrons. We find that the equivalent of as much as an eight times increase to the plasma loss rate would be needed to reconcile the sub-Mch model with observed spectra. Future studies could distinguish between reductions in the non-thermal ionisation rates and increased recombination rates, such as by clumping., 13 pages. Accepted by MNRAS

Purpose Pharmacists are well positioned to provide transitions of care (TOC) services to patients with heart failure (HF); however, hospitalizations for patients with HF likely exceed the capacity of a TOC pharmacist. We developed and validated a tool to help pharmacists efficiently identify high-risk patients with HF and maximize their potential impact by intervening on patients at the highest risk for 30-day all-cause readmission. Methods We conducted a retrospective cohort study including adults with HF admitted to a health system between October 1, 2016, and October 31, 2019. We randomly divided the cohort into development (n = 2,114) and validation (n = 1,089) subcohorts. Nine models were applied to select the most important predictors of 30-day readmission. The final tool, called the Tool for Pharmacists to Predict 30-day hospital readmission in patients with Heart Failure (ToPP-HF) relied upon multivariable logistic regression. We assessed discriminative ability using the C statistic and calibration using the Hosmer-Lemeshow goodness-of-fit test. Results The risk of 30-day all-cause readmission was 15.7% (n = 331) and 18.8% (n = 205) in the development and validation subcohorts, respectively. The ToPP-HF tool included 13 variables: number of hospital admissions in previous 6 months; admission diagnosis of HF; number of scheduled medications; chronic obstructive pulmonary disease diagnosis; number of comorbidities; estimated glomerular filtration rate; hospital length of stay; left ventricular ejection fraction; critical care requirement; renin-angiotensin-aldosterone system inhibitor use; antiarrhythmic use; hypokalemia; and serum sodium. Discriminatory performance (C statistic of 0.69; 95% confidence interval [CI], 0.65-0.73) and calibration (Hosmer-Lemeshow P = 0.28) were good. Conclusions The ToPP-HF performs well and can help pharmacists identify high-risk patients with HF most likely to benefit from TOC services.

STUDY DESIGN: This was a case series. OBJECTIVE: The authors sought to examine the high-risk population of COVID-positive patients with acute cervical spinal cord injury (SCI) in a large level 1 trauma and tertiary referral center. SUMMARY OF BACKGROUND DATA: There are limited studies regarding the surgical management of patients with acute SCI in the setting of the recent coronavirus pandemic. METHODS: The authors describe the cases of 2 patients who died from COVID-related complications after acute cervical SCI. RESULTS: Patients with SCI are at increased risk of pulmonary complications. COVID-19 infection represents a double hit in this patient population, increasing potential morbidity and mortality in the perioperative time frame. Careful consideration must be made regarding the timing of potential surgical intervention in the treatment of acute SCI. CONCLUSIONS: Nationwide database of COVID-positive patients with acute spinal cord injury should be collected and analyzed to better understand how to manage acute SCI in the COVID-19 era. The authors recommend preoperative discussion in patients with acute cervical SCI with COVID-19, specifically emphasizing the increased risk of respiratory complications and mortality.

Purpose To describe the pharmacokinetics of flucytosine in a critically ill patient undergoing continuous venovenous hemodiafiltration (CVVHDF) treated for cryptococcal meningitis. Summary A 20-year-old female weighing 93.4 kg with a body mass index of 34.3 kg/m2 with a past medical history of systemic lupus erythematous with diffuse proliferative lupus nephritis (class IV) was admitted to the hospital after several months of worsening dyspnea, fatigue, myalgia, vomiting, and diarrhea. The patient developed worsening renal function and volume overload requiring CVVHDF on hospital day 7. She was diagnosed with cryptococcal meningitis on hospital day 8, and flucytosine 2,500 mg enterally every 12 hours and liposomal amphotericin B 500 mg intravenously every 24 hours were initiated. Flucytosine serum concentrations were collected on day 4 of therapy, and pharmacokinetics were performed on 2 sequential levels. Pharmacokinetic calculations displayed an elimination rate constant of 0.0338 h-1, a volume of distribution between 0.42 and 0.43 L/kg, a half-life of 20.5 hours, and a total drug clearance between 1.32 and 1.36 L/h while on CVVHDF. The nonsequential levels displayed good correlation, and no further monitoring or dosage adjustment was required. The patient completed therapy, with clinical resolution of her infection, and no toxicities due to flucytosine were noted. Conclusion Flucytosine dosed at 25 mg/kg of actual body weight every 12 hours during CVVHDF conferred therapeutic levels with no appreciable toxicities. Because of its narrow therapeutic index and risk of toxicity, additional pharmacokinetic studies are needed to determine optimal drug dosing of this medication in patients requiring renal replacement therapy.

We present the first results of a comprehensive supernova (SN) radiative-transfer (RT) code-comparison initiative (StaNdaRT), where the emission from the same set of standardized test models is simulated by currently-used RT codes. A total of ten codes have been run on a set of four benchmark ejecta models of Type Ia supernovae. We consider two sub-Chandrasekhar-mass ($M_\mathrm{tot} = 1.0$ M$_\odot$) toy models with analytic density and composition profiles and two Chandrasekhar-mass delayed-detonation models that are outcomes of hydrodynamical simulations. We adopt spherical symmetry for all four models. The results of the different codes, including the light curves, spectra, and the evolution of several physical properties as a function of radius and time, are provided in electronic form in a standard format via a public repository. We also include the detailed test model profiles and several python scripts for accessing and presenting the input and output files. We also provide the code used to generate the toy models studied here. In this paper, we describe in detail the test models, radiative-transfer codes and output formats and provide access to the repository. We present example results of several key diagnostic features., Accepted for publication in A&A. 27 pages, 12 figures (v4: updated to match published version). The ejecta models and output files from the simulations are available at https://github.com/sn-rad-trans/data1

Double detonations of sub-Chandrasekhar mass white dwarfs are a promising explosion scenario for Type Ia supernovae, whereby a detonation in a surface helium shell triggers a secondary detonation in a carbon-oxygen core. Recent work has shown that low mass helium shell models reproduce observations of normal SNe Ia. We present 3D radiative transfer simulations for a suite of 3D simulations of the double detonation explosion scenario for a range of shell and core masses. We find light curves broadly able to reproduce the faint end of the width-luminosity relation shown by SNe Ia, however, we find that all of our models show extremely red colours, not observed in normal SNe Ia. This includes our lowest mass helium shell model. We find clear Ti II absorption features in the model spectra, which would lead to classification as peculiar SNe Ia, as well as line blanketing in some lines of sight by singly ionised Cr and Fe-peak elements. Our radiative transfer simulations show that these explosion models remain promising to explain peculiar SNe Ia. Future full non-LTE simulations may improve the agreement of these explosion models with observations of normal SNe Ia., Comment: Spectra available at https://doi.org/10.5281/zenodo.7997388

This study was designed to explore the relationship between participation (measured by percentage of time spoken) in team-based learning (TBL) exercises and final examination in a 4-week medical microbiology course for college students from backgrounds underrepresented in medicine (URM). A significant correlation was found between participation and examination scores in lower performing students. Although male participation was higher, a significant correlation between participation and examination scores was found only in females. These data suggest that female participation is based on knowledge of the subject under discussion and that affirmation in TBL positively reinforces self-confidence, increasing student’s efficiency during peer teaching.

Background: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. Methods: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at −6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. Results: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at −6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL ( p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL ( p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h ( p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h ( p-value: 0.188) for adults. Conclusion: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.

PurposeThe purpose of this study was to demonstrate the utility of failure modes and effects analysis (FMEA) for systematically identifying potential sources of controlled substance diversion and developing solutions in an academic health system.MethodsThe FMEA was conducted by an 18-member cross-functional team from the department of pharmacy. The team developed scoring criteria specifically for controlled substance diversion, outlined the controlled substance processes from procurement to administration or disposal, and identified ways in which each step of the medication supply process might fail (failure modes) and result in diversion of controlled substances. Failure modes with a vulnerability score of 48 or 64 were considered highest risk and were immediately intervened on by the FMEA team.ResultsThe FMEA outlined a total of 10 major steps and 30 substeps in the controlled substance supply process. From this, 103 potential failure modes were identified, with 24 modes (23%) receiving a vulnerability score of 48 or 64. Development of specific reports addressed 15 failure modes, while 9 involved pharmacy workflow alterations. Notable reports included controlled substance activity under temporary patients and discrepancy trends by user, medication, and patient care area. Notable workflow alterations included expanded use of cameras in high-risk areas and additional verification checks.ConclusionFMEA allowed for systematic identification of controlled substance diversion opportunities, prioritization by level of vulnerability, and the development of targeted strategies to reduce risk of diversion.

Significance Malaria remains a major global health threat. In the face of increasing resistance to available chemotherapeutics, new antimalarial drugs with new modes of action are urgently needed. The causative agent of malaria is a single-celled parasite that invades and replicates within red blood cells. Escape from the red cell, a process called egress, involves a proteolytic pathway triggered by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and rational optimization of a potent, membrane-permeable substrate-based boronic acid compounds that block egress and parasite proliferation by direct inhibition of SUB1 activity. The compounds could form the basis of a new type of antimalarial medicine that would both protect against infection and treat disease., Malaria is a devastating infectious disease, which causes over 400,000 deaths per annum and impacts the lives of nearly half the world’s population. The causative agent, a protozoan parasite, replicates within red blood cells (RBCs), eventually destroying the cells in a lytic process called egress to release a new generation of parasites. These invade fresh RBCs to repeat the cycle. Egress is regulated by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and optimization of substrate-based peptidic boronic acids that inhibit Plasmodium falciparum SUB1 with low nanomolar potency. Structural optimization generated membrane-permeable, slow off-rate inhibitors that prevent P. falciparum egress through direct inhibition of SUB1 activity and block parasite replication in vitro at submicromolar concentrations. Our results validate SUB1 as a potential target for a new class of antimalarial drugs designed to prevent parasite replication and disease progression.

Double detonations in sub-Chandrasekhar mass carbon-oxygen white dwarfs with helium shell are a potential explosion mechanism for a Type Ia supernova (SNe Ia). It comprises a shell detonation and subsequent core detonation. The focus of our study is on the effect of the progenitor metallicity on the nucleosynthetic yields. For this, we compute and analyse a set of eleven different models with varying core and shell masses at four different metallicities each. This results in a total of 44 models at metallicities between 0.01$Z_\odot$ and 3$Z_\odot$. Our models show a strong impact of the metallicity in the high density regime. The presence of $^{22}$Ne causes a neutron-excess which shifts the production from $^{56}$Ni to stable isotopes such as $^{54}$Fe and $^{58}$Ni in the $\alpha$-rich freeze-out regime. The isotopes of the metallicity implementation further serve as seed nuclei for additional reactions in the shell detonation. Most significantly, the production of $^{55}$Mn increases with metallicity confirming the results of previous work. A comparison of elemental ratios relative to iron shows a relatively good match to solar values for some models. Super-solar values are reached for Mn at 3$Z_\odot$ and solar values in some models at $Z_\odot$. This indicates that the required contribution of SNe Ia originating from Chandrasekhar mass WDs can be lower than estimated in orevious work to reach solar values of [Mn/Fe] at [Fe/H]$=0$. Our galactic chemical evolution models suggest that SNe Ia from sub-Chandrasekhar mass white dwarfs, along with core-collapse supernovae, could account for more than 80% of the solar Mn abundance. Using metallicity-dependent SN Ia yields helps to reproduce the upward trend of [Mn/Fe] as a function of metallicity for the solar neighborhood. These chemical evolution predictions, however, depend on the massive star yields adopted in the calculations., Comment: accepted for publication by A&A

PurposeThe high-value pharmacy enterprise (HVPE) framework and constituent best practice consensus statements are presented, and the methods used to develop the framework’s 8 domains are described.SummaryA panel of pharmacy leaders used an evidence- and expert opinion–based approach to define core and aspirational elements of practice that should be established within contemporary health-system pharmacy enterprises by calendar year 2025. Eight domains of an HVPE were identified: Patient Care Services; Business Services; Ambulatory and Specialty Pharmacy Services; Inpatient Operations; Safety and Quality; Pharmacy Workforce; Information Technology, Data, and Information Management; and Leadership. Phase 1 of the project consisted of the development of draft practice statements, performance elements, and supporting evidence for each domain by panelists, followed by a phase 2 in-person meeting for review and development of consensus for statements and performance elements in each domain. During phase 3, the project cochairs and panelists finalized the domain drafts and incorporated them into a full technical report and this summary report.ConclusionThe HVPE framework is a strategic roadmap to advance pharmacy practice by ensuring safe, effective, and patient-centered medication management and business practices throughout the health-system pharmacy enterprise. Grounded in evidence and expert recommendations, the statements and associated performance elements can be used to identify strategic priorities to improve patient outcomes and add value within health systems.

Background How corticosteroid use affects treatment response to chemotherapy and immune-checkpoint inhibitors (CICPIs) remains unknown. We assessed how systemic corticosteroid exposure before CICPI modifies the effect of CICPI on outcomes among patients with metastatic non-small cell lung cancer (mNSCLC) or extensive-stage small-cell lung cancer (ES-SCLC). Methods We conducted a retrospective cohort study using electronic health records to examine patients with mNSCLC or ES-SCLC who received chemotherapy (CT) between 1st April 2015 and 31st January 2018 or CICPI between 1st February 2018 and 31st August 2019. We excluded those with an actionable driver mutation. Baseline corticosteroid use was defined as systemic corticosteroids within 28 days before the initiation of CT or CICPI, not including premedications. Coprimary outcomes included overall survival (OS), real-world progression (rwP), and real-world progression-free survival (rwPFS) in CICPI-treated corticosteroid users versus non-users. We used inverse probability of treatment weighting (IPW) to adjust for potential confounding. Results The cohort of 316 patients (median [interquartile range] age, 67 [61–73] years; 156 [49%] male) included 228 CT-treated and 88 CICPI-treated patients. After applying IPW, characteristics were well-balanced between the CT and CICPI groups, and steroid users and non-users. Using CT-treated steroid non-users as a common comparator, CICPI-treated steroid users were as likely as CICPI-treated steroid non-users to die (users IPW hazard ratio [HR] = 0.67, 95% CI = 0.35–1.28 versus non-users IPW-HR = 0.88, 95% C = I0.55–1.42; p = 0.49), have rwP (IPW-HR = 0.35, 95% C = I0.12–0.99 versus IPW-HR = 0.41, 95% C = I0.24–0.70; p = 0.77), or experience rwPFS (IPW-HR = 0.56, 95% C = I0.29–1.09 versus IPW-HR = 0.69, 95% CI0.46–1.03; p = 0.59). Conclusion Corticosteroid use before CICPIs was not associated with worse outcomes, suggesting that corticosteroids should be used with CICPIs when indicated.

Sub-Chandrasekhar mass carbon-oxygen white dwarfs with a surface helium shell have been proposed as progenitors of Type Ia supernovae (SNe Ia). If true, the resulting thermonuclear explosions should be able to account for at least some of the range of SNe Ia observables. To study this, we conducted a parameter study based on three-dimensional simulations of double detonations in carbon-oxygen white dwarfs with a helium shell, assuming different core and shell masses. An admixture of carbon to the shell and solar metallicity are included in the models. The hydrodynamic simulations were carried out using the AREPO code. This allowed us to follow the helium shell detonation with high numerical resolution, and this improves the reliability of predicted nucleosynthetic shell detonation yields. The addition of carbon to the shell leads to a lower production of 56Ni, while including solar metallicity increases the production of intermediate mass elements. The production of higher mass elements is further shifted to stable isotopes at solar metallicity. Moreover, we find different core detonation ignition mechanisms depending on the core and shell mass configuration. This has an influence on the ejecta structure. We present the bolometric light curves predicted from our explosion simulations using the Monte Carlo radiative transfer code ARTIS and make comparisons with bolometric SNe Ia data. The bolometric light curves of our models show a range of brightnesses, which is able to account for subluminous to normal brightness SNe Ia. We show the model bolometric width-luminosity relation compared to data for a range of model viewing angles. We find that, on average, our brighter models lie within the observed data. The ejecta asymmetries produce a wide distribution of observables, which might account for outliers in the data. However, the models overestimate the extent of this compared to data. We also find that the bolometric decline rate over 40 days, Δm40(bol), appears systematically faster than data.

Red blood cell (RBC) invasion by malaria merozoites involves formation of a parasitophorous vacuole into which the parasite moves. The vacuole membrane seals and pinches off behind the parasite through an unknown mechanism, enclosing the parasite within the RBC. During invasion, several parasite surface proteins are shed by a membrane-bound protease called SUB2. Here we show that genetic depletion of SUB2 abolishes shedding of a range of parasite proteins, identifying previously unrecognized SUB2 substrates. Interaction of SUB2-null merozoites with RBCs leads to either abortive invasion with rapid RBC lysis, or successful entry but developmental arrest. Selective failure to shed the most abundant SUB2 substrate, MSP1, reduces intracellular replication, whilst conditional ablation of the substrate AMA1 produces host RBC lysis. We conclude that SUB2 activity is critical for host RBC membrane sealing following parasite internalisation and for correct functioning of merozoite surface proteins., eLife digest Malaria kills or disables hundreds of millions of people across the world, especially in developing economies. The most severe form of the disease is caused by Plasmodium falciparum, a single-cell parasite which, once inside a human host, forces its way into red blood cells to feed on a protein called haemoglobin. This invasion relies on P. falciparum being engulfed by the membrane of the red blood cell, which then seals off to form a compartment inside the cell where the parasite can feed and multiply. Invasion takes less than 30 seconds, and it involves P. falciparum losing the coat of proteins that covers its surface. An enzyme calls SUB2 cleaves or cuts off these proteins, but exactly why and how the shedding takes place during infection is still unclear. To investigate, Collins, Hackett et al. deactivated the gene which codes for SUB2, and examined how mutant P. falciparum would survive and multiply. Without the enzyme, the parasites failed to shed many of their proteins, including some that were not previously known to be removed by SUB2. The majority of the genetically modified parasites also failed to invade red blood cells. In particular, most of the host cells ruptured, suggesting that the protein coat needs to be discarded for the engulfing process to be completed properly. When the enzyme-free mutants did manage to make their way into a red blood cell, they starved to death because they could not digest haemoglobin. SUB2 and surface coat shedding therefore appears to be essential for the parasite to survive. P. falciparum is fast becoming resistant to the many drugs that exist to fight malaria. New treatments that target SUB2 may therefore help in combatting this deadly disease.

Pediatric delirium is common, associated with negative patient outcomes, and infrequently assessed in the ICU. Locally, pediatric delirium assessments in the cardiac PICU were infrequently documented resulting in an initiative to increase assessment documentation and implement a nurse-driven management protocol, the Bundle to Eliminate Delirium (BED).This was a nurse-driven, quality improvement project in an eleven-bed cardiac PICU at a large academic health care facility. A pre- and postimplementation survey evaluating delirium management perceptions, knowledge, and assessment barriers was emailed to 113 nurses. Nurses received education about general delirium principles and assessment followed by weekly emails that included delirium assessment documentation rates and targeted education. Subsequently, BED education was provided via email followed by BED implementation, inclusion of BED completion rates in weekly emails, and observational audits of BED implementation.1522 delirium assessment opportunities were evaluated. Assessment documentation increased by 33%. Nurses reported greater confidence in their ability to manage delirium (P.05 for numerous aspects of delirium care) and were less likely to report 'positive delirium assessments not acted upon' as a barrier to delirium assessment. BED implementation was inconsistent.Nursing education and feedback can increase delirium assessment rates and confidence in management but the impact of BED on these outcomes is not clear.Improvement in pediatric delirium care may be obtained through a nurse-driven quality improvement project but an interprofessional approach is needed for optimal management. More studies are needed to identify effective pediatric delirium management strategies such as the BED.

OBJECTIVE: To compare sustained virologic response 12 weeks post-treatment completion (SVR12) and patient characteristics for older versus younger patients with chronic hepatitis C virus infection (HCV) receiving direct-acting antiviral (DAA) agent therapy. METHODS: This retrospective cohort study included patients with chronic HCV who received DAA therapy, between 2015 and 2018, in the largest health system in Rhode Island (N=154). Patient characteristics, comorbid diagnoses, and SVR12 status were compared between older (aged ≥60 years) and younger (

Sub-Chandrasekhar mass white dwarfs accreting a helium shell on a carbon-oxygen core are potential progenitors of normal Type Ia supernovae. This work focuses on the details of the onset of the carbon detonation in the double detonation sub-Chandrasekhar model. In order to simulate the influence of core-shell mixing on the carbon ignition mechanism, the helium shell and its detonation are followed with an increased resolution compared to the rest of the star treating the propagation of the detonation wave more accurately. This significantly improves the predictions of the nucleosynthetic yields from the helium burning. The simulations were carried out with the AREPO code. A carbon-oxygen core with a helium shell was set up in one dimension and mapped to three dimensions. We ensured the stability of the white dwarf with a relaxation step before the hydrodynamic detonation simulation started. Synthetic observables were calculated with the radiative transfer code ARTIS. An ignition mechanism of the carbon detonation was observed, which received little attention before. In this "scissors mechanism", the impact the helium detonation wave has on unburnt material when converging opposite to its ignition spot is strong enough to ignite a carbon detonation. This is possible in a carbon enriched transition region between the core and shell. The detonation mechanism is found to be sensitive to details of the core-shell transition and our models illustrate the need to consider core-shell mixing taking place during the accretion process. Even though the detonation ignition mechanism differs form the converging shock mechanism, the differences in the synthetic observables are not significant. Though they do not fit observations better than previous simulations, they illustrate the need for multi-dimensional simulations., Comment: Accepted for publication in A&A

Objectives To determine whether best practice advisories improved sedation protocol compliance and could mitigate potential propofol-related hazardous conditions. Design Retrospective observational cohort study. Setting Two adult ICUs at two academic medical centers that share the same sedation protocol. Patients Adults 18 years old or older admitted to the ICU between January 1, 2016, and January 31, 2018, who received a continuous infusion of propofol. Interventions Two concurrent best practice advisories built in the electronic health record as a clinical decision support tool to enforce protocol compliance with triglyceride and lipase level monitoring and mitigate propofol-related hazardous conditions. Measurements and main results The primary outcomes were baseline and day 3 compliance with triglyceride and lipase laboratory monitoring per protocol and time to discontinuation of propofol in the setting of triglyceride and/or lipase levels exceeding protocol cutoffs. A total of 1,394 patients were included in the study cohort (n = 700 in the pre-best practice advisory group; n = 694 in the post-best practice advisory group). In inverse probability weighted regression analyses, implementing the best practice advisory was associated with a 56.6% (95% CI, 52.6-60.9) absolute increase and a 173% relative increase (risk ratio, 2.73; 95% CI, 2.45-3.04) in baseline laboratory monitoring. The best practice advisory was associated with a 34.0% (95% CI, 20.9-47.1) absolute increase and a 74% (95% CI, 1.39-2.19) relative increase in day 3 laboratory monitoring after inverse probability weighted analyses. Among patients with laboratory values exceeding protocol cutoffs, implementation of the best practice advisory resulted in providers discontinuing propofol an average of 16.6 hours (95% CI, 4.8-28.3) sooner than pre-best practice advisory. Findings from alternate analyses using interrupted time series were consistent with the inverse probability weighted analyses. Conclusions Best practice advisories can be effectively used in ICUs to improve sedation protocol compliance and may mitigate potential propofol-related hazardous conditions. Best practice advisories should undergo continuous quality assurance and optimizations to maximize clinical utility and minimize alert fatigue.

Context Injuries in professional ultimate Frisbee (ultimate) athletes have never been described. Objective To determine injury rates, profiles, and associated factors using the first injury-surveillance program for professional ultimate. Design Descriptive epidemiology study. Setting American Ultimate Disc League professional ultimate teams during the 2017 season. Patients or Other Participants Sixteen all-male teams. Main Outcome Measure(s) Injury incidence rates (IRs) were calculated as injuries per 1000 athlete-exposures (AEs). Incidence rate ratios were determined to compare IRs with 95% confidence intervals, which were used to calculate differences. Results We observed 299 injuries over 8963 AEs for a total IR of 33.36 per 1000 AEs. Most injuries affected the lower extremity (72%). The most common injuries were thigh-muscle strains (12.7%) and ankle-ligament sprains (11.4%). Running was the most frequent injury mechanism (32%). Twenty-nine percent of injuries involved collisions; however, the concussion rate was low (IR = 0.22 per 1000 AEs). Injuries were more likely to occur during competition and in the second half of games. An artificial turf playing surface did not affect overall injury rates (Mantel-Haenszel incidence rate ratio = 1.28; 95% confidence interval = 0.99, 1.67). Conclusions To our knowledge, this is the first epidemiologic study of professional ultimate injuries. Injury rates were comparable with those of similar collegiate- and professional-level sports.

Introduction Guidelines recommend pegfilgrastim for primary prophylaxis of febrile neutropenia after highly myelosuppressive chemotherapy. While deviations from guidelines could result in overuse and increased costs, underuse is also a concern and could compromise quality of care. Our objectives were to evaluate guideline adherence and quantify the extent to which physician heterogeneity may influence pegfilgrastim use. Methods We randomly sampled 550 patients from a retrospective cohort of those who received infusions at an academic cancer center between 1 September 2013 and 1 September 2014. Electronic medical and drug dispensing records provided information on patient characteristics, chemotherapy characteristics, prescribing physician, and pegfilgrastim administration. Results We included 154 patients treated by 25 physicians. About half of patients were male and mean age was 61.3 years. Forty (26.1%) patients had no febrile neutropenia risk factors, 62 (40.5%) had one, and 51 (33.3%) had two or more. Thirty patients (19.5%) received pegfilgrastim, of which 12 (40%) received palliative chemotherapy. Nine (60%) of 15 patients on a regimen with a febrile neutropenia risk ≥ 20% received pegfilgrastim. Pegfilgrastim use significantly varied by cancer type (p Conclusion Pegfilgrastim was potentially overused for palliative chemotherapy and underused for chemotherapy regimens with febrile neutropenia risk ≥ 20%. Successful interventions to modify prescribing practices likely require an understanding of the relationship between specific physician characteristics and pegfilgrastim use.

BACKGROUND: A multidisciplinary approach is recommended for the management of type 2 diabetes mellitus (DM). AIM: To evaluate the impact of a pharmacist intervention on haemoglobin A1c (HbA(1c)), systolic blood pressure (SBP), diastolic blood pressure (DBP), and diabetes-related hospitalisations in an underserved cohort with unmanaged type 2 DM. METHODS: This analysis was a retrospective cohort study. Criteria for inclusion were persons with unmanaged type 2 DM defined as HbA(1c) values ≥8% at time of enrolment, ≥18 years old, and enrolment in a pharmacist-managed clinic for ≥12 months. Pre- and post-intervention differences in HbA(1c), SBP and DBP values were assessed using repeated measures analysis of variance (ANOVA). The risk of diabetes-related hospitalisations was estimated during the 12 months prior and during the 12 months post-intervention, and the relative risk (RR) was calculated. RESULTS: Mean HbA(1c) values at 3, 6 and 12 months post-intervention were lower than baseline values (p < 0.05). There was no significant difference in mean HbA(1c) values at 6 or 12 months compared to 3 months post intervention. Mean SBP values at 3, 6 and 12 months were lower than baseline (p < 0.05). Likewise, mean DBP values at 6 and 12 months were lower than baseline (p < 0.05). The estimated RR of diabetes-related hospitalisations was 0.40 (95% CI: 0.20–0.83; p = 0.013). CONCLUSION: Enrolment in a pharmacist-managed diabetes program was associated with a significant reduction in HbA1c, SBP and DBP and reduction in risk of diabetes-related hospitalisations in an underserved cohort of patients with diabetes over a 12-month period.

Introduction Quantifying patient outcomes is integral in orthopaedic practice, and patient-reported outcome measures (PROMs) assist with this goal and assist clinicians in assessing subjective outcomes (pain, satisfaction, etc.). This study seeks to identify the most highly used PROMs in the shoulder literature and analyze their usage trends. Methods PubMed was queried for all shoulder-based articles published in eight selected journals from 2007 to 2017. Articles were assessed for PROM usage, surgical approach, surgical procedure, and disease pathology. Frequency analyses identified the most used PROMs overall, and for each approach, procedure, and pathology. Last, usage trends, question number, validation, and clinician dependence of PROMs with ≥20 uses were analyzed. Results In total, 1,740 of 2,462 articles (71%) used 105 unique PROMs 4,394 times during the study. PROM usage increased 18%, and the use of multiple PROMs increased by 20%. PROMs with a clinician component increased 21% slower than the baseline. Twenty-two PROMs (17%) had >20 uses, with the most used PROMs being the Constant-Murley Score (783), American Shoulder and Elbow Surgeons Shoulder Score (731), Visual Analog Scale (685), Simple Shoulder Test (372), and the University of California, Los Angeles, Shoulder Rating Scale (274). PROMs demonstrating the greatest usage increase were the EuroQol 5-Dimensions Questionnaire (1,282%), Shoulder Pain and Disability Index (638%), Western Ontario Rotator Cuff Index (632%), Western Ontario Osteoarthritis of the Shoulder Index (582%), and Oxford Shoulder Score (462%)-all without a clinician component. Discussion PROM usage is increasing, often with multiple PROMs being used to evaluate patient outcomes. PROMs without a clinician component are growing at higher rates than their clinician-dependent counterparts, highlighting an emphasis on patient reporting of outcomes. This study suggests that the American Shoulder and Elbow Surgeons Shoulder Score, Oxford Shoulder Score, Visual Analog Scales-all without a mandatory clinician component and high levels of use-will be the most highly used PROMs moving forward to assess shoulder function.

Background Although landmark trials in the metastatic (CLEOPATRA) and neo-adjuvant (NeoSphere; TRYPHAENA) settings identified all-grade diarrhea as a pertuzumab-associated adverse event, it was not classified as dose-limiting. In actual practice, diarrhea is often a reason for treatment modifications. Objectives To compare the risk of pertuzumab-associated diarrhea in actual practice to the risks in randomized controlled trials. Methods We conducted a retrospective cohort study of HER2/neu-positive breast cancer patients who received a pertuzumab-containing regimen between January 2012 and August 2015. We calculated the risk of diarrhea with 95% confidence limits (CLs), and then used two-sample t-tests to compare the risk between trials and actual practice. Results A total of 27 patients in the study cohort received a pertuzumab-containing treatment regimen for HER2/neu-positive breast cancer. The overall risk of all-grade and severe diarrhea in actual practice was 70% (95% CLs 55–90%) and 37% (95% CLs 20–66%), respectively. No severe diarrhea was observed in the metastatic setting, and the risk of all-grade diarrhea (44%, 95% CLs 21–92%) was similar to the CLEOPATRA study (67%). The risk of all-grade diarrhea in the neo-adjuvant setting was 83% (95% CLs 68–100%), compared to 46% in the NeoSphere trial (p = 0.03). The risk of severe diarrhea (Grade 3–4) in the neo-adjuvant setting was 47% (95% CLs 27–80%) versus 6% in the NeoSphere (p Conclusions The risk of all-grade and severe diarrhea associated with neoadjuvant pertuzumab use for HER2/neu-positive breast cancer was greater in actual practice than in trials.

Background Secondary prevention medications are often not prescribed to frail, older adults following acute myocardial infarction, potentially because of the absence of data to support use, perceived lack of benefit, and concern over possible harms. We examined the effect of using more guideline-recommended medications after myocardial infarction on mortality, rehospitalization, and functional decline in the frailest and oldest segment of the US population—long-stay nursing home residents. Methods and Results We conducted a retrospective cohort study of nursing home residents aged ≥65 years using 2007 to 2010 national US Minimum Data Set clinical assessment data and Medicare claims. Exposure was the number of secondary prevention medications (antiplatelets, β-blockers, statins, and renin-angiotensin-aldosterone system inhibitors) initiated after myocardial infarction. Outcomes were 90-day death, rehospitalization, and functional decline. We compared outcomes for new users of 2 versus 1 and 3 or 4 versus 1 medications using the inverse probability of treatment-weighted odds ratios with 95% CI. The cohort comprised 4787 residents, with a total of 509 death, 820 functional decline, and 1226 rehospitalization events. Compared with individuals who initiated 1 medication, mortality odds ratios were 0.98 (95% CI, 0.79–1.22) and 0.74 (95% CI, 0.57–0.97) for users of 2 and 3 or 4 medications, respectively. Rehospitalization odds ratios were 1.00 (95% CI, 0.85–1.17) for 2 and 0.97 (95% CI, 0.8–1.17) for 3 or 4 medications. Functional decline odds ratios were 1.04 (95% CI, 0.85–1.28) for 2 and 1.12 (95% CI, 0.89–1.40) for 3 or 4 medications. In a stability analysis excluding antiplatelet drugs from the exposure definition, more medication use was associated with functional decline. Conclusions Use of more guideline-recommended medications after myocardial infarction was associated with decreased mortality in older, predominantly frail adults, but no difference in rehospitalization. Results for functional decline from the main and stability analyses were discordant and did not rule out an increased risk associated with more medication use.

Purpose The optimal health care delivery models for providing services to patients with infections caused by hepatitis C virus (HCV) remain unknown. Pharmacist involvement may be a key component of optimal HCV care delivery. We examined the comparative effectiveness of a pharmacist-managed HCV clinic versus a pharmacist-assisted HCV clinic. Methods This retrospective cohort study used electronic health record data on patients ≥18 years old initiating HCV treatment at a pharmacist-managed clinic or a pharmacist-assisted clinic within a single health-system between January 2015 and June 2017. Outcomes included treatment completion, sustained virologic response 12 weeks following treatment completion (SVR-12), and dispensation of direct-acting antiviral agents at the institution-based specialty pharmacy. Inverse probability of treatment-weighted (IPTW) logistic regression models were used to compare outcomes between the 2 clinic models. Results A total of 127 patients initiated HCV treatment therapy: 64 patients from the pharmacist-managed clinic and 63 patients from the pharmacist-assisted clinic. The cohort had a mean age of 55 years, was 51% male, and 68% white. In IPTW analyses, there was no difference in treatment completion (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.1-13.8; p = 0.93), achievement of sustained virologic response at 12 months (SVR-12) (OR, 1.0; 95% CI, 0.2-4.5; p = 0.62), or use of institution-based specialty pharmacy (OR, 0.6; 95% CI, 0.2-1.7; p = 0.33) between pharmacist-managed and pharmacist-assisted clinics. Conclusion There were no significant differences in outcomes between patients receiving care at the pharmacist-managed HCV clinic and the pharmacist-assisted clinic. Given the frequency of SVR-12 achieved in both groups, both pharmacist-managed and pharmacist-assisted clinic models may be reasonable alternatives for providing outpatient HCV care.

We extend the range of validity of the ARTIS 3D radiative transfer code up to hundreds of days after explosion, when Type Ia supernovae are in their nebular phase. To achieve this, we add a non-local thermodynamic equilibrium (non-LTE) population and ionisation solver, a new multi-frequency radiation field model, and a new atomic dataset with forbidden transitions. We treat collisions with non-thermal leptons resulting from nuclear decays to account for their contribution to excitation, ionisation, and heating. We validate our method with a variety of tests including comparing our synthetic nebular spectra for the well-known one-dimensional W7 model with the results of other studies. As an illustrative application of the code, we present synthetic nebular spectra for the detonation of a sub-Chandrasekhar white dwarf in which the possible effects of gravitational settling of Ne22 prior to explosion have been explored. Specifically, we compare synthetic nebular spectra for a 1.06 M$_\odot$ white dwarf model obtained when 5.5 Gyr of very-efficient settling is assumed to a similar model without settling. We find that this degree of Ne22 settling has only a modest effect on the resulting nebular spectra due to increased Ni58 abundance. Due to the high ionisation in sub-Chandrasekhar models, the nebular [Ni II] emission remains negligible, while the [Ni III] line strengths are increased and the overall ionisation balance is slightly lowered in the model with Ne22 settling. In common with previous studies of sub-Chandrasekhar models at nebular epochs, these models overproduce [Fe III] emission relative to [Fe II] in comparison to observations of normal Type Ia supernovae., Comment: 15 pages, 12 figures. Accepted for publication by MNRAS

The density of cells and neurons in the neocortex of many mammals varies across cortical areas and regions. This variability is, perhaps, most pronounced in primates. Nonuniformity in the composition of cortex suggests regions of the cortex have different specializations. Specifically, regions with densely packed neurons contain smaller neurons that are activated by relatively few inputs, thereby preserving information, whereas regions that are less densely packed have larger neurons that have more integrative functions. Here we present the numbers of cells and neurons for 742 discrete locations across the neocortex in a chimpanzee. Using isotropic fractionation and flow fractionation methods for cell and neuron counts, we estimate that neocortex of one hemisphere contains 9.5 billion cells and 3.7 billion neurons. Primary visual cortex occupies 35 cm(2) of surface, 10% of the total, and contains 737 million densely packed neurons, 20% of the total neurons contained within the hemisphere. Other areas of high neuron packing include secondary visual areas, somatosensory cortex, and prefrontal granular cortex. Areas of low levels of neuron packing density include motor and premotor cortex. These values reflect those obtained from more limited samples of cortex in humans and other primates.

According to previous research, cell and neuron densities vary across neocortex in a similar manner across primate taxa. Here, we provide a more extensive examination of this effect in macaque monkeys. We separated neocortex from the underlying white matter in 4 macaque monkey hemispheres (1 Macaca nemestrina, 2 Macaca radiata, and 1 Macaca mulatta), manually flattened the neocortex, and divided it into smaller tissue pieces for analysis. The number of cells and neurons were determined for each piece across the cortical sheet using flow cytometry. Primary visual cortex had the most densely packed neurons and primary motor cortex had the least densely packed neurons. With respect to differences in brain size between cases, there was little variability in the total cell and neuron numbers within specific areas, and overall trends were similar to what has been previously described in Old World baboons and other primates. The average hemispheric total cell number per hemisphere ranged from 2.9 to 3.7 billion, while the average total neuron number ranged from 1.3 to 1.7 billion neurons. The visual cortex neuron densities were predictably higher, ranging from 18.2 to 34.7 million neurons/cm2 in macaques, in comparison to a range of 9.3-17.7 million neurons/cm2 across cortex as a whole. The results support other evidence that neuron surface densities vary across the cortical sheet in a predictable pattern within and across primate taxa.