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Introduction: Proximal tibia physeal fractures in children are not very common but can be dangerous because they can harm popliteal fossa structures, especially the popliteal artery. Popliteal artery injuries (PAI) are most commonly the result of trauma to the lower extremity, including blunt force, hyperextension injuries, complex fractures, and knee dislocations that can compromise popliteal neurovascular structures. Case Presentation. A 14-year-old boy presents to the emergency department after being transferred from an outside hospital 24 hours after a left lower extremity hyperextension injury. Radiographs demonstrated a Salter-Harris III proximal tibia fracture with posterior displacement. ABIs were deferred due to palpable distal pulses and no evidence of compartment syndrome. Closed reduction and percutaneous pinning were planned to correct the fracture. Intraoperatively, it was discovered that knee extension decreased lower extremity perfusion while knee flexion returned perfusion. An angiography revealed a popliteal artery occlusion with no distal flow. Based on this, an above-knee to below-knee popliteal bypass using the contralateral great saphenous vein was performed followed by closed reduction and percutaneous pinning of the proximal tibia., Conclusion: Proximal tibia physeal injuries, especially the Salter-Harris III and IV injuries, warrant a high index of suspicion of popliteal artery injuries. Palpable pulses and delayed presentation in the distal lower extremity do not rule out a PAI because collateral flow to the anterior and posterior tibial arteries may mask signs of an avascular limb, highlighting the need for a thorough history and physical exam. The authors present this case to reaffirm the importance of an ankle-brachial index when evaluating hyperextension injuries with proximal tibial epiphyseal fractures., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Alexandra H. Seidenstein et al.)

Malaria results in over 600,000 deaths annually, with the highest burden of deaths in young children living in sub-Saharan Africa. Molecular surveillance can provide important information for malaria control policies, including detection of antimalarial drug resistance. However, genome sequencing capacity in malaria-endemic countries is limited. We designed and implemented an end-to-end workflow to detect Plasmodium falciparum antimalarial resistance markers and diversity in the vaccine target circumsporozoite protein (csp) using nanopore sequencing in Ghana. We analysed 196 clinical samples and showed that our method is rapid, robust, accurate and straightforward to implement. Importantly, our method could be applied to dried blood spot samples, which are readily collected in endemic settings. We report that P. falciparum parasites in Ghana are mostly susceptible to chloroquine, with persistent sulfadoxine-pyrimethamine resistance and no evidence of artemisinin resistance. Multiple single nucleotide polymorphisms were identified in csp, but their significance is uncertain. Our study demonstrates the feasibility of nanopore sequencing for malaria genomic surveillance in endemic countries., (© 2023. The Author(s).)

Microplastics are created for commercial use, are shed from textiles, or result from the breakdown of larger plastic items. Recent reports have shown that microplastics accumulate in human tissues and may have adverse health consequences. Currently, there are no standardized environmental monitoring systems to track microplastic accumulation within human tissues. Using Raman spectroscopy, we investigated the temporal exposures to plastic pollution in Hawai'i and noted a significant increase in the accumulation of microplastics in discarded placentas over the past 15 years, with changes in the size and chemical composition of the polymers. These findings provide a rare insight into the vulnerability and sensitivity of Pacific Island residents to plastic pollution and illustrate how discarded human tissues can be used as an innovative environmental plastic pollution monitoring system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Atom probe tomography (APT) is a powerful materials characterization technique capable of measuring the isotopically resolved three-dimensional (3D) structure of nanoscale specimens with atomic resolution. Modern APT instrumentation most often uses an optical pulse to trigger field ion evaporation-most commonly, the second or third harmonic of a Nd laser is utilized (∼λ = 532 nm or λ = 355 nm). Herein, we describe an APT instrument that utilizes ultrafast extreme ultraviolet (EUV) optical pulses to trigger field ion emission. The EUV light is generated via a commercially available high harmonic generation system based on a noble-gas-filled capillary. The centroid of the EUV spectrum is tunable from around 25 eV (λ = 50 nm) to 45 eV (λ = 28 nm), dependent on the identity of the gas in the capillary (Xe, Kr, or Ar). EUV pulses are delivered to the APT analysis chamber via a vacuum beamline that was optimized to maximize photon flux at the APT specimen apex while minimizing complexity. We describe the design of the beamline in detail, including the various compromises involved. We characterize the spectrum of the EUV light and its evolution as it propagates through the various optical elements. The EUV focus spot size is measured at the APT specimen plane, and the effects of misalignment are simulated and discussed. The long-term stability of the EUV source has been demonstrated for more than a year. Finally, APT mass spectra are shown, demonstrating the instrument's ability to successfully trigger field ion emission from semiconductors (Si, GaN) and insulating materials (Al2O3).

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 MalariaGEN et al.)

Background: Chimeric antigen receptor (CAR) T-cell therapy provides effective treatment for large B-cell lymphoma (LBCL). Cost-utility analyses examining and comparing the value of these treatments require health state utilities representing key characteristics to differentiate among therapies. This study estimated utilities for adverse events (AEs) associated with CAR T-cell therapy, including cytokine release syndrome (CRS) and neurological events (NEs)., Methods: Health state vignettes were drafted based on literature review, AE reports from a trial of CAR T-cell therapy, and clinician input. Health states were valued in time trade-off interviews with general population participants in the UK. The first vignette described relapsed/refractory LBCL treated with CAR T-cell therapy without AEs. Five other vignettes had the same LBCL and treatment description, with the addition of an AE. Disutilities (i.e., utility decrease) associated with these AEs were calculated by subtracting the utility of the health state without AEs from those of the other health states., Results: Interviews were completed with 218 participants (50% male; mean age 49 years). Mean (standard deviation [SD]) utility for CAR T-cell therapy without AEs was 0.73 (0.30). Mean (SD) disutilities associated with CRS were -0.01 (0.04) for grade 1, -0.05 (0.09) for grade 2, and -0.23 (0.24) for grade 3/4. Mean (SD) disutilities associated with NEs were -0.04 (0.07) for grade 1/2 and -0.18 (0.22) for grade 3/4., Conclusions: More severe AEs were associated with greater disutilities. Health state utilities estimated in this study may be useful in cost-effectiveness models examining the value of CAR T-cell therapy in patients with LBCL., (© 2022. The Author(s).)

Audience: Emergency medicine interns, medical students, and mid-level providers (physician assistants, nurse practitioners)., Introduction: Shock is defined as a state of global tissue hypoxia and is typically the result of hypotension and circulatory system failure. A variety of disease states may ultimately culminate in hypotensive shock through one or more generally recognized mechanisms - hypovolemic, cardiogenic, obstructive, and/or distributive shock.1 These mechanisms differ significantly in terms of their pathophysiology and requisite treatment. While the effects of hypotensive shock are initially reversible, untreated hypotensive shock may rapidly progress to multiorgan failure and death. Hence, the ability to promptly recognize a state of hypotensive shock, identify the underlying mechanism, and administer appropriate therapies are skills required of those caring for critically ill patients.2The evaluation of hypotensive shock in the Emergency Department is relatively commonplace. Mortality rates associated with shock are high, ranging from 22.6% - 56.2%, depending upon the underlying etiology.3 For these reasons, the authors believe that a web-based learning module addressing topics related to hypotensive shock would be beneficial to healthcare professionals who are likely to encounter it in clinical practice. The web-based nature of the module would lend itself to convenient viewing and would allow for utilization as a just-in-time training modality. Presenting these topics in an animated format may also be a useful way of displaying the complex nature of cardiovascular physiology., Educational Objectives: By the end of this module, participants should be able to:Review basic principles of cardiovascular physiologyDescribe the four general pathophysiologic mechanisms of hypotensive shockRecognize various etiologies for each mechanism of hypotensive shockRecognize differences in the clinical presentation of each mechanism of hypotensive shockCite the basic approach to treatment for each mechanism of hypotensive shock., Educational Methods: This is a video podcast which conveys information through animated content. It is available to learners on demand and just-in-time for practice. It may be used as a stand-alone educational tool, as a primer to other instructional methods (eg, simulation, flipped classroom setting, or case discussions), or a just-in-time training tool., Research Methods: A small-scale study was performed to quantify the efficacy of this module as an educational tool. The learner group was comprised of a convenience sample of third-year medical students in the midst of their core clinical clerkships. All third-year students were eligible to participate, regardless of which core clerkship they were currently engaged in. Third-year students were contacted via email regarding participation. Participation was completely optional - no incentive was offered, and students were informed that participation would not in any way affect their clerkship grades. For these reasons, an Instructional Review Board review was not necessary. Ten third-year medical students volunteered to participate. In the course of a single, hour-long session, learners were administered the attached assessment form as a pre-test, shown the video module, and then asked to immediately retake the assessment as a post-test to assess for improvement. Assessments were graded on a 17-point scale, according to the attached answer key. Learners were also given the opportunity to provide subjective feedback on the quality of the module as an educational tool., Results: For this assessment, the maximum possible score was 17 points. The average pre-test score across all learners was 11.75 (69.12%) with a standard deviation of 3.24. The average post-test score across all learners was 15.12 (88.97%) with a standard deviation of 3.31. All learners demonstrated improvement in scores on the post-test, with a maximum and minimum improvement of 6 points and 1 point respectively. On average, learners improved by 3.38 points (p = 0.029, 95% confidence interval, 1.97 to 4.78). Statistical significance was established using a paired student's T-test. All learners agreed with the statement, "This module effectively taught concepts related to hypotensive shock." Learners were also given the opportunity to provide subjective feedback regarding the module and responded with statements like, "comprehensive review of the subject," and "very helpful review for clinical clerkships.", Discussion: Data from learner assessments suggest that this module is effective in communicating concepts related to hypotensive shock. Learner satisfaction with the module was unanimous. These results suggest that this module would be effective as a standalone educational tool, or as a primer to other instructional methods. Areas of further investigation may include assessment of a larger learner population, assessment of learners at additional stages of clinical training, and assessment of long-term knowledge retention., Topics: Shock, hypotension, cardiovascular physiology, pulmonary artery catheterization, flipped classroom, asynchronous learning, emergency medicine., (© 2022 MacDonald, et al.)

Excited state lifetimes of neutral titanium oxide clusters (Ti n O 2n-x , n < 10, x < 4) were measured using a sequence of 400 nm pump and 800 nm probe femtosecond laser pulses. Despite large differences in electronic properties between the closed shell stoichiometric Ti n O 2n clusters and the suboxide Ti n O 2n-x (x = 1-3) clusters, the transient responses for all clusters contain a fast response of 35 fs followed by a sub-picosecond (ps) excited state lifetime. In this non-scalable size regime, subtle changes in the sub-ps lifetimes are attributed to variations in the coordination of Ti atoms and localization of charge carriers following UV photoexcitation. In general, clusters exhibit longer lifetimes with increased size and also with the addition of O atoms. This suggests that the removal of O atoms develops stronger Ti-Ti interactions as the system transitions from a semiconducting character to a fast metallic electronic relaxation mechanism.

Excited state lifetimes of neutral Cr 2 O n ( n < 5) clusters were measured using femtosecond pump-probe spectroscopy. Density functional theory calculations reveal that the excited state dynamics are correlated with changes in the cluster's electronic structure with increasing oxidation. Upon absorption of a UV (400 nm) photon, the clusters exhibit features attributed to three separate relaxation processes. All clusters exhibit similar subpicosecond lifetimes, attributed to vibrational relaxation. However, the ∼30 fs transient signal fraction grows linearly with oxidation, matching the amount of O to Cr charge transfer character of the photoexcitation and highlighting a gradual transition between semiconducting and metallic behavior at the molecular level. A long-lived (>2.5 ps) response is recorded only in clusters with significant d-electron character, suggesting that adiabatic relaxation back to the ground state is efficient in heavily oxidized clusters, due to the presence of terminal O atoms. The simple picture of sequential oxidation of Cr 2 O n reveals a linear variation in the contributions of each relaxation component to the total transient signals, therefore opening possibilities for the design of new molecular spintronic materials.

Introduction: We previously examined how expanding access to chimeric antigen receptor (CAR) T cell therapy administration sites impacted patient travel distances and time. In the current study, we estimated travel-related economic burden associated with site-of-care options among patients with relapsed/refractory diffuse large B cell lymphoma., Methods: We used geographic information system methods to quantify travel-related economic burden across three site-of-care scenarios: academic hospitals; academic and community multispecialty hospitals; and academic and community multispecialty hospitals plus nonacademic specialty oncology network centers. Socioeconomic status, administration sites, and county of residence were derived from the US Census Bureau and publicly available sources. Travel costs were based on governmental guidelines, US census wage data, and Bureau of Transportation Statistics. Travel distance and time to the nearest CAR T cell therapy administration sites were estimated from previous research., Results: Total national estimated costs associated with traveling for CAR T cell therapy were $21.1 million if CAR T cell therapy was offered exclusively in academic hospitals, and $14.7 million if expanded to include community hospitals plus nonacademic specialty oncology network centers, representing a $6.5-million reduction associated with expanding access to eligible patients. The largest cost-saving component was lodging/meals. Regional and demographic cost differences were statistically significant between academic hospitals and nonacademic hospitals/specialty oncology centers. In all scenarios, patients living below the federal poverty level (FPL) had higher weighted mean total costs versus patients living above the FPL. White and Native American patients were estimated to have the highest weighted mean total costs across race/ethnicity groups. For all subgroups, costs were reduced by expanding access beyond academic hospitals., Conclusion: CAR T cell therapy is currently restricted to academic hospitals; total travel costs could be substantially decreased if access is expanded to nonacademic hospitals and specialty oncology centers. Patients in rural areas and those living below the FPL are particularly disadvantaged by restricted access., (© 2021. The Author(s).)

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 MalariaGEN et al.)

Most patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have exhausted their treatment options and are deemed palliative. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has recently been introduced as a new option for these patients. Lisocabtagene maraleucel (liso-cel) is an investigational CAR T-cell therapy that has shown promising activity in this setting. We used an unanchored matching-adjusted indirect comparison (MAIC) methodology to compare liso-cel, using individual patient-level data from the TRANSCEND NHL 001 (TRANSCEND; NCT02631044) trial, to salvage chemotherapy, using summary-level data from the SCHOLAR-1 study, for the treatment of patients with R/R LBCL. Standardized mean differences were used to evaluate imbalances between the TRANSCEND and SCHOLAR-1 studies. MAIC was conducted to determine the relative efficacy of liso-cel vs. salvage chemotherapy with regard to overall survival, complete response rate, and objective response rate. For all efficacy outcomes assessed, comparisons of clinical factors before MAIC showed that five of seven baseline characteristics were similar between the TRANSCEND and SCHOLAR-1 studies; however, age and R/R to last therapy status differed between studies, thus requiring matching and adjusting to ensure the validity of this analysis. The base case analyses demonstrated a significantly lower risk of mortality (hazard ratio, 0.5; 95% confidence interval [CI] 0.4-0.6; p < 0.001) with significantly higher rates of complete response (odds ratio, 12.9; 95% CI 8.0-20.7) and objective response (odds ratio, 7.0; 95% CI 4.6-10.5) for patients treated with liso-cel than patients treated with salvage chemotherapy. MAIC comparisons demonstrated favorable efficacy for liso-cel compared with salvage chemotherapy in the treatment of patients with R/R LBCL.Trial Registration ClinicalTrials.gov identifier: NCT02631044.

Neutral titanium oxide clusters of up to 1 nm in diameter (TiO 2 ) n , with n < 10, are produced in a laser vaporization source and subsequently ionized by a sequence of femtosecond laser pulses. Using a 400 nm pump and 800 nm probe lasers, the excited state lifetimes of neutral (TiO 2 ) n clusters are measured. All clusters exhibit a rapid relaxation lifetime of ∼35 fs, followed by a sub-picosecond lifetime that we attribute to carrier recombination. The excited state lifetimes oscillate with size, with even-numbered clusters possessing longer lifetimes. Density functional theory calculations show the excited state lifetimes are correlated with charge carrier localization or polaron-like formation in the excited states of neutral clusters. Thus, structural rigidity is suggested as a feature for extending excited state lifetimes in titania materials.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown efficacy as a third-line or later treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire, we evaluated the impact of CAR T-cell treatment with lisocabtagene maraleucel (liso-cel) on health-related quality of life (HRQoL) and symptoms in patients with relapsed/refractory LBCL in the ongoing, open-label, nonrandomized TRANSCEND NHL 001 trial. Clinically meaningful improvement was observed in EORTC QLQ-C30 scores for global health status/QoL, based on a minimally important difference of 10 points at 2 to 18 months after liso-cel infusion. There were no clinically meaningful changes in physical functioning and pain, whereas clinically meaningful improvements were observed in fatigue at 2, 12, and 18 months. The proportion of patients with clinically meaningful improvement in global health status/QoL was generally higher for treatment responders than for nonresponders. A trend toward decreased mean EQ-5D-5L index scores was observed at 1 month after liso-cel infusion, followed by subsequent increases through 18 months. Mean EQ-5D-5L visual analog scale scores increased from 2 through 18 months. In summary, patients with relapsed/refractory LBCL treated with liso-cel had early, sustained, and clinically meaningful improvements in HRQoL and symptoms that correlated with antitumor activity. This study was registered at www.clinicaltrials.gov as #NCT02631044., (© 2021 by The American Society of Hematology.)

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell-specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044., (© 2021 by The American Society of Hematology.)

Neutral iron oxide clusters (FenOm, n, m ≤ 16) are produced in a laser vaporization source using O2 gas seeded in He. The neutral clusters are ionized with a sequence of femtosecond laser pulses and detected using time-of-flight mass spectrometry. Small clusters are confirmed to be most prominent in the stoichiometric (n = m) distribution, with m = n + 1 clusters observed above n = 4. Pump-probe spectroscopy is employed to study the dynamics of an electron transfer from an oxygen orbital to an iron nonbonding orbital of iron oxide clusters that is driven by absorption of a 400 nm photon. A bifurcation of the initial wavepacket occurs, where a femtosecond component is attributed to electron relaxation assisted through internuclear vibrational relaxation and high density of states, and a slow relaxation shows the formation of a bound excited state. The lifetime and relative ratio of the two pathways depend on both the cluster size and iron oxidation state. The femtosecond lifetime decreases with increased cluster size until a saturation timescale is achieved at n > 5. The relative population of the long-lived excited state decreases with cluster size and suggests that the excited electron remains on the Fe atom for >20 ps.

Background: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas., Methods: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 10 6 CAR + T cells [one or two doses], 100 × 10 6 CAR + T cells, and 150 × 10 6 CAR + T cells), which were administered as a sequential infusion of two components (CD8 + and CD4 + CAR + T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044., Findings: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR + T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 10 6 CAR + T cells (50 × 10 6 CD8 + and 50 × 10 6 CD4 + CAR + T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 10 6 CAR + T cells., Interpretation: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies., Funding: Juno Therapeutics, a Bristol-Myers Squibb Company., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sternoclavicular joint (SCJ) instability is a rare condition and results from either a traumatic high energy impact, such as a motor vehicle crash or contact sports injury, or non-traumatically as a result of structural pathology. The infrequency of this injury has contributed to its diagnosis being missed as well as the paucity of literature on treatment and outcomes. Patients with SCJ instability often report diminished range of motion as well as shoulder girdle pain. The presentation of instability in the sternoclavicular joint can vary in severity and anterior or posterior directionality. Variation in severity of the instability changes the course of treatment regarding either operative or non-operative interventions to stabilize the SCJ. In general, anterior instability of the SCJ (the medial clavicle is displaced anterior to the sternum) is less urgent and generally manageable by symptom alleviation and rehabilitation, although some anterior instability cases require surgical intervention. In the case of posterior SCJ instability (the medial clavicle is displaced posterior to the sternum), patients require prompt joint reduction as they are at the greater risk of life-threatening injury due to the location of critical structures of the mediastinum posterior to the SCJ. Computed tomography visualization is useful to confirm dislocation or subluxation direction to better formulate a proper treatment plan. The purpose of this review is to report the clinical presentation and management of SCJ instability including pertinent symptoms, the diagnostic approaches to evaluating SCJ instability, as well as operative and non-operative management of the joint instability., Competing Interests: Dr. Brent Ponce reports personal fees from Wright Medical Inc, personal fees from ODi, personal fees from Mitek, personal fees from Stryker, outside the submitted work. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connections with the submitted article. Additionally, there was no grant support or other funding methods associated with this article., (© 2020 Garcia et al.)

Audience: Emergency medicine residents (interns, junior residents), medical students, and mid-level providers (physician assistants, nurse practitioners)., Introduction: Pneumothorax refers to the presence of gas within the pleural space and is a relatively common clinical entity in the emergency department.1 Traumatic pneumothorax results from blunt or penetrating trauma to the thorax. Iatrogenic pneumothorax is a risk inherent to a number of invasive procedures and represents a significant cause of preventable morbidity.2 Specifically, central venous catheterization (43.8%), thoracentesis (20.1%), and barotrauma due to mechanical ventilation (9.1%) are the most frequent causes.3A feared complication of pneumothorax is the development of tension pneumothorax, which involves the compression of mediastinal structures by increased pressures within the pleural space, leading to hemodynamic compromise.4 As tension pneumothorax is an emergent, life-threatening condition, the management of pneumothorax and the insertion of chest tubes are skills required of physicians involved in the care of injured patients, including general surgeons, intensivists, and emergency medicine physicians.5 The process of correcting pneumothorax is not without complication. Complications following chest tube insertion in trauma patients occur in 19% of cases,6 and are commonly a result of chest tubes placed by resident physicians.7The authors believe that a web-based learning module addressing topics related to pneumothorax (pathophysiology, clinical manifestations, diagnosis, and management) would be beneficial to healthcare providers who are likely to encounter pneumothorax in clinical practice. Specifically, the web-based nature of the module would lend itself to convenient viewing and would allow for utilization as a just-in-time training modality. Presenting these topics in an animated format may also be a useful way of capturing the complex and three-dimensional nature of respiratory physiology. Additionally, the web-based format may be particularly appealing to digital native natives, who occupy an increasing percentage of resident physician positions.8 It should be noted that a number of studies have examined the use of computerized modules in medical education, and found them to be at least as useful as traditional instructional methods, and are typically associated with high rates of satisfaction among learners.9-13., Educational Objectives: By the end of this module, participants should be able to:Review the normal physiology of the pleural spaceDiscuss the pathophysiology of pneumothoraxDescribe the clinical presentation of pneumothoraxIdentify pneumothorax on a chest radiographReview treatment options for pneumothorax., Educational Methods: This is a video podcast, which conveys information through animated content. It is available to learners on demand and just-in-time for practice. It may be used as a stand-alone educational tool, as a primer to other instructional methods (eg, simulation), or a just-in-time training tool., Research Methods: A small-scale study was conducted to evaluate the efficacy of this module as an educational tool. The learner group consisted of a convenience sample of 11 second-year medical students at the end of their pre-clinical training. All learners were administered the attached assessment form as a pre-test, shown the video, then asked to re-take the assessment as a post-test to assess improvement. Assessments were graded on a 10-point scale according to the attached answer key. Learners were also given the opportunity to rate the quality of the module as an educational tool, as well as to provide subjective feedback., Results: The average pre-test score across all learners was 34%. The average post-test score across all learners was 82%, representing an improvement of 48%. Learners were asked to rate their agreement with the statements, "This module effectively taught concepts related to pulmonary physiology and pneumothorax," and, "The animated format of this module was useful for illustrating concepts related to pulmonary physiology and pneumothorax." All learners responded with "agree" or "strongly agree" for each statement. When given the opportunity to provide subjective feedback regarding the module, learners responded with "This module is a great review! It is well organized, has effective animations, and information is clear," and "Helpful review that explained the concepts in an accessible way!", Discussion: Results from the pre-test and post-test suggest that this module was effective in teaching concepts related to pulmonary physiology and pneumothorax. All learners reported satisfaction with the animated format in particular. These results suggest that this module would be effective as a standalone educational tool or as a primer to other instructional methods., Topics: Pneumothorax, thoracostomy, needle decompression, flipped classroom, asynchronous learning, emergency medicine., (© 2020 MacDonald, et al.)

Purpose: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC., Methods: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models., Results: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality., Conclusions: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Metabolic obstacles of the tumor microenvironment remain a challenge to T-cell-mediated cancer immunotherapies. To better understand the interplay of immune checkpoint signaling and immune metabolism, this study developed and used an optimized metabolite extraction protocol for non-adherent primary human T-cells, to broadly profile in vitro metabolic changes effected by PD-1 signaling by mass spectrometry-based metabolomics and isotopomer analysis. Inhibitory signaling reduced aerobic glycolysis and glutaminolysis. A general scarcity across the panel of metabolites measured supported widespread metabolic regulation by PD-1. Glucose carbon fate analysis supported tricarboxylic acid cycle reliance on pyruvate carboxylation, catabolic-state fluxes into acetyl-CoA and succinyl-CoA, and a block in de novo nucleoside phosphate synthesis that was accompanied by reduced mTORC1 signaling. Nonetheless, exogenous administration of nucleosides was not sufficient to ameliorate proliferation of T-cells in the context of multiple metabolic insufficiencies due to PD-L1 treatment. Carbon fate analysis did not support the use of primarily glucose-derived carbons to fuel fatty acid beta oxidation, in contrast to reports on T-memory cells. These findings add to our understanding of metabolic dysregulation by PD-1 signaling and inform the effort to rationally develop metabolic interventions coupled with immune-checkpoint blockade for increased treatment efficacy., Competing Interests: Conflict of interestT.G.G. reports receiving honoraria from Amgen, having consulting and equity relationships with Trethera Corporation. The lab of T.G.G. has completed a research agreement with ImmunoActiva. A.R. reports personal fees from consulting with Amgen, Chugai, Genentech-Roche, Novartis, Merck, Sanofi, and being a member of the scientific advisory board of Arcus, Bioncotech, Compugen, Cytomx, Five Prime, FLX-Bio, Merus, Rgenix, PACT Pharma, and Tango Therapeutics., (© The Author(s) 2019.)

Individual malaria infections can carry multiple strains of Plasmodium falciparum with varying levels of relatedness. Yet, how local epidemiology affects the properties of such mixed infections remains unclear. Here, we develop an enhanced method for strain deconvolution from genome sequencing data, which estimates the number of strains, their proportions, identity-by-descent (IBD) profiles and individual haplotypes. Applying it to the Pf3k data set, we find that the rate of mixed infection varies from 29% to 63% across countries and that 51% of mixed infections involve more than two strains. Furthermore, we estimate that 47% of symptomatic dual infections contain sibling strains likely to have been co-transmitted from a single mosquito, and find evidence of mixed infections propagated over successive infection cycles. Finally, leveraging data from the Malaria Atlas Project, we find that prevalence correlates within Africa, but not Asia, with both the rate of mixed infection and the level of IBD., Competing Interests: SZ, JH, JA, RP, RA, AM, DW, TL, MN, PG, DK, GM No competing interests declared, (© 2019, Zhu et al.)

Background: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer., Patients and Methods: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models., Results: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality., Conclusion: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports., Methods: We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus., Findings: We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia., Interpretation: The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia., Funding: Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs., Methods: A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines., Results: The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes., Conclusions: Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.

Background: As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong subregion, emerging resistance to partner drugs in artemisinin combination therapies seriously threatens global efforts to treat and eliminate this disease. Molecular markers that predict failure of artemisinin combination therapy are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in southeast Asia and beyond., Methods: We did a genome-wide association study of 297 P falciparum isolates from Cambodia to investigate the relationship of 11 630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC 50 s), and tested whether these genetic variants are markers of treatment failure with dihydroartemisinin-piperaquine. We then did a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin-piperaquine treatment., Findings: Piperaquine IC 50 s increased significantly from 2011 to 2013 in three Cambodian provinces (2011 vs 2013 median IC 50 s: 20·0 nmol/L [IQR 13·7-29·0] vs 39·2 nmol/L [32·8-48·1] for Ratanakiri, 19·3 nmol/L [15·1-26·2] vs 66·2 nmol/L [49·9-83·0] for Preah Vihear, and 19·6 nmol/L [11·9-33·9] vs 81·1 nmol/L [61·3-113·1] for Pursat; all p≤10 -3 ; Kruskal-Wallis test). Genome-wide analysis of SNPs identified a chromosome 13 region that associates with raised piperaquine IC 50 s. A non-synonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin-piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdr1 gene on chromosome 5 and a novel amplification of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 also associate with raised piperaquine IC 50 s. After adjusting for covariates, both exo-E415G and plasmepsin 2-3 markers significantly associate (p=3·0 × 10 -8 and p=1·7 × 10 -7 , respectively) with decreased treatment efficacy (survival rates 0·38 [95% CI 0·25-0·51] and 0·41 [0·28-0·53], respectively)., Interpretation: The exo-E415G SNP and plasmepsin 2-3 amplification are markers of piperaquine resistance and dihydroartemisinin-piperaquine failures in Cambodia, and can help monitor the spread of these phenotypes into other countries of the Greater Mekong subregion, and elucidate the mechanism of piperaquine resistance. Since plasmepsins are involved in the parasite's haemoglobin-to-haemozoin conversion pathway, targeted by related antimalarials, plasmepsin 2-3 amplification probably mediates piperaquine resistance., Funding: Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and UK Department for International Development., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice., Methods: A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred., Results: Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable., Conclusions: In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.

Purpose: To describe patient- and practice-related factors that physicians report affect their clinical decision to administer prophylactic pegfilgrastim to patients <24 h after completion of a myelosuppressive chemotherapy cycle (i.e., "same-day" pegfilgrastim)., Methods: Oncologists, hematologists, and hematologist-oncologists enrolled in a US national physician panel were invited to participate in a cross-sectional, web-based survey to assess physicians' reasons for prescribing "same-day" pegfilgrastim. Physicians were screened as eligible if they reported prescribing "same-day" pegfilgrastim within the previous 6 months. The survey assessed physician perspectives and physician-perceived patient/caregiver preferences., Results: Of 17,478 invited physicians, 386 answered the screening questions; 151 (39.1 %) were eligible, agreed to participate, and completed the survey. Physicians estimated that overall 41.3 % of their patients treated with myelosuppressive chemotherapy received pegfilgrastim and that 31.6 % treated with pegfilgrastim received it on a "same-day" schedule. Approximately 36 % of physicians relied primarily on their clinical judgment when deciding to administer "same-day" pegfilgrastim. The clinical consideration reported most commonly by physicians as moderately or very important when deciding to administer "same-day" pegfilgrastim was previous febrile neutropenia (77.6 %). The most important patient-related consideration in the decision to administer "same-day" pegfilgrastim was patient/caregiver travel distance, and the most important practice-related consideration was the burden to the physician's practice of "next-day" administration (vs. same-day), reported by 84.7 % and 65.1 % of physicians as moderately or very important, respectively., Conclusions: While clinical judgment, patients' risk factors, and practice burden were principal influences favoring "same-day" pegfilgrastim administration, physician-perceived patient preferences and logistical barriers also have important roles in this decision.

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region and analyzed data on >300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax., Competing Interests: The authors declare no competing financial interests.

Purpose: Accumulating evidence suggests that not all cancer chemotherapy patients who receive first-cycle pegfilgrastim prophylaxis continue to receive it in subsequent cycles and that these patients may be subsequently at higher risk of febrile neutropenia (FN). Additional evidence from US clinical practice is warranted., Methods: Data from two US private healthcare claims repositories were employed. The source population comprised adults who received "intermediate-risk" or "high-risk" chemotherapy regimens for solid cancers or non-Hodgkin's lymphoma and first-cycle pegfilgrastim prophylaxis. From the source population, all patients who did not receive second-cycle pegfilgrastim prophylaxis ("comparison patients") were matched (1:1) to those who received it ("pegfilgrastim patients") based on cancer, regimen, and propensity score. Odds ratios (OR) for FN-broad and narrow definitions-during the second chemotherapy cycle were estimated for comparison patients versus pegfilgrastim patients using generalized estimating equations., Results: A total of 2245 comparison patients (5.3 % of source population) were matched to pegfilgrastim patients; cohorts were well-balanced on baseline characteristics. Second-cycle FN incidence proportions for comparison and pegfilgrastim patients were 3.8 versus 2.2 % based on broad definition and 2.6 versus 0.8 % based on narrow definition; corresponding OR were 1.7 (95 % CI 1.2-2.5, p = 0.002) and 3.5 (95 % CI 2.0-6.0, p < 0.001). Results were similar within cancer/regimen-subgroups and were robust when using alternative methods for confounding adjustment., Conclusions: In this retrospective evaluation of cancer chemotherapy patients who received first-cycle pegfilgrastim prophylaxis in US clinical practice, a clinically relevant minority did not receive second-cycle prophylaxis. Second-cycle FN odds among this subset were significantly higher than they were among those who continued prophylaxis.

Pancreatic islet transplantation has been validated as a treatment for type 1 diabetes since it maintains consistent and sustained type 1 diabetes reversal. However, one of the major challenges in pancreatic islet transplantation is the body's natural immune response to the implanted islets. Immunosuppressive drug treatment is the most popular immunomodulatory approach for islet graft survival. However, administration of immunosuppressive drugs gives rise to negative side effects, and long-term effects are not clearly understood. A bioartificial pancreas is a therapeutic approach to enable pancreatic islet transplantation without or with minimal immune suppression. The bioartificial pancreas encapsulates the pancreatic islets in a semi-permeable environment which protects islets from the body's immune responses, while allowing the permeation of insulin, oxygen, nutrients, and waste. Many groups have developed various types of the bioartificial pancreas and tested their efficacy in animal models. However, the clinical application of the bioartificial pancreas still requires further investigation. In this review, we discuss several types of bioartificial pancreases and address their advantages and limitations. We also discuss recent advances in bioartificial pancreas applications with microfluidic or micropatterning technology.

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7&#95;1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

The authors explored relationships among childhood abuse, suicidal ideation, and sexual orientation of 18- to 30-year-old students enrolled in 2 San Diego area colleges, using responses from anonymous questionnaires. Sixty percent of the 138 eligible respondents were women, and 22% were self-identified gay/bisexual individuals. Women were more likely than men to report at least 1 form of emotional abuse (odds ratio [OR] = 2.3; p =.02) and unwanted sexual touching (OR = 4.3; p = .0004). Lesbian/bisexual women were significantly more likely to report past suicidal ideation than were heterosexual women (OR = 3.7, p = .03). Gay/bisexual men were more likely to report unwanted sexual touching than were heterosexual men (OR = 5.1, p = .04), but the men did not report significantly higher rates of past suicide ideation or suicide attempts. Sexual orientation and a past history of child sexual, physical, and emotional abuse could be compounding risk factors for suicidal ideation among college students.