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BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).

PURPOSE: (18) F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas. In addition, we examined the time to repeat scan and the rate of pseudoprogression within this population. Lastly, the rates of radiographic response to CART therapy using FDG PET/CT are reported. PROCEDURES: The pre-treatment and post-treatment scans were analyzed from a selected cohort of 43 patients from a single institution. Patients were stratified by diagnosis of either a first occurrence of diffuse large B-cell lymphoma: de novo diffuse large B-cell lymphoma (DLBCL); or a transformed diffuse large B-cell lymphoma arising from indolent non-Hodgkin lymphoma (t-iNHL). RESULTS: More patients received CART therapy for DLBCL than t-iNHL (65% vs 35%). FDG PET/CT had a 99% sensitivity and 100% specificity for detecting recurrent disease in this group. The median time to initial response assessment was 86 days (IQR 79-91; full range 24-146) after infusion. There were no biopsy-proven cases of pseudoprogression identified. In this selected group of patients, the overall response rate by Lugano 2014 criteria was 56%. All patients with a partial response (N = 6) eventually progressed despite additional therapy. CONCLUSIONS: Due to its excellent test characteristics and ability to detect asymptomatic disease, routine surveillance with PET/CT at 3 months after CART infusion is supported by our data. Earlier PET/CT may be of value in select situations as we did not find any cases of pseudoprogression.

Cell-cell interactions and communication are crucial to the proper function of complex mammalian physiology including neurocognitive and immune system functions. While many tools are available for observing and perturbing intracellular processes, relatively few exist to probe intercellular processes. Current techniques for studying interactions often rely on direct protein contact, and few can manipulate diverse, functional outputs with tunable protein expression. To address these limitations, we have developed a small-molecule approach based on a trimethoprim prodrug-enzyme pair capable of reporting the presence of two different engineered cell populations with programmable protein outputs. The approach relies on bacterial nitroreductase enzyme catalysis, which is orthogonal to normal mammalian biology, and diffusion of trimethoprim from "activator" cells to "receiver" cells. We test this strategy, which can theoretically regulate many different types of proteins, using biochemical and in vitro culture assays with optical and cytokine protein readouts. This describes the first small-molecule approach capable of detecting and controlling engineered cell-cell outputs, and we anticipate future applications that are especially relevant to the field of immuno-oncology.

Recently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.One Sentence SummaryThe PET radiotracer [11C]-trimethoprim shows high uptake in both TMP-sensitive and -resistant bacteria in vitro, the potential for imaging many different pathogenic strains, and uptake in patients with active infections.

The anticipated growth and urbanization of the global population over the next several decades will create a vast demand for the construction of new housing, commercial buildings and accompanying infrastructure. The production of cement, steel and other building materials associated with this wave of construction will become a major source of greenhouse gas emissions. Might it be possible to transform this potential threat to the global climate system into a powerful means to mitigate climate change? To answer this provocative question, we explore the potential of mid-rise urban buildings designed with engineered timber to provide long-term storage of carbon and to avoid the carbon-intensive production of mineral-based construction materials. Increasing urbanization will lead to a significant expansion of buildings and related infrastructure, major sources of greenhouse gas emissions. This Perspective discusses the possibility of constructing mid-rise urban buildings with engineered timber for long-term carbon storage and carbon emissions reduction.

Cp*Ir(pyridinesulfonamide)Cl (Cp* = pentamethylcyclopentadienyl) precatalysts 1–7 are active for the transfer hydrogenation of aryl, alkyl, and heterocyclic aldehydes. Catalysis is conducted under base-free conditions in air without dried or degassed substrates and solvents. These reductions occur rapidly in moderate to high conversion (39–100%). Benzaldehyde derivatives are reduced to alcohols within 30 min at 85 °C using 1 mol% iridium precatalyst; reduction also occurs at lower temperatures and loadings (60 °C, 0.50 mol% precatalyst). Benzaldehyde derivatives that possess electron-rich and electron-poor substituents in the para position, including base-sensitive 4-hydroxybenzaldehyde, are readily reduced. Aryl aldehydes containing electron-poor groups are reduced faster than substrates possessing electron-rich moieties. Reduction of the positional isomers of methoxybenzaldehyde and isopropylbenzaldehyde shows highest reduction for the ortho isomer, followed by the meta isomer. Heterocyclic substrates, including biomass derived 5-hydroxymethylfurfural and 2-furfural, were reduced selectively to the alcohol. Decyl aldehyde was reduced to the linear alcohol; importantly self-condensation was not observed. Competition studies demonstrated selective reduction of aldehydes over ketones and a mercury poisoning experiment supports a homogeneous catalyzed pathway.

N-(2-(Pyridin-2-yl)ethyl)benzenesulfonamide derivatives and 1,1,1-trifluoro-N-(2-(pyridin-2-yl)ethyl)methanesulfonamide (1–4), along with three-legged piano stool Cp*IrIIICl complexes (5–11) (Cp* = pentamethylcyclopentadienyl) bearing pyridinesulfonamide ligands with varying electronic parameters, were synthesized. These ligands and air-stable complexes were characterized by 1H and 13C{1H} NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. Precatalysts, 5–11, were assessed for transfer hydrogenation of aryl, diaryl, dialkyl, linear, cycloaliphatic, and α,β-unsaturated ketones, diones, β-ketoesters, and a biomass-derived substrate with 2-propanol, using 1 mol % precatalyst. Catalysis was also efficient using a 0.1 mol % loading. Remarkably, all catalysis experiments can be conducted in air without dried and degassed substrates, and basic additives and halide abstractors are not required for high activity in transfer hydrogenation. Control experiments and a mercury poisoning experim...

ARTICLES NEW PASSWORDS IN THE VISA AND WORK PERMIT GAME: A REVIEW OF THE NEW VISA AND WORK PERMIT REGULATORY FRAMEWORK IN TAIWAN Robin Winklert Robert Leett Andrew Ruffttt TABLE OF CONTENTS I. INTRODUCTION II. GOVERNMENT ATTITUDES TOWARD IMMIGRATION AND NATURALIZATION ..... A. General Background: Economic Setting ........ B. Visas and Working: The Labor Market for Foreign Nationals C. Visas and Working: Government Approvals ... D. Visas and Working: Government Attitudes .... III. VISITOR VISAS AND WORK AUTHORIZATION A . O verview B. Temporary Visitors C. Visas Granted for the Purpose of Employment 1. Sales Volume 2. Other Requirements t Robin Winkler is a Partner with the firm Koo, Winkler, Hsu & Hwang. He has practiced law in Taiwan for fifteen years and publishes frequently on topics rang- ing from employment to intellectual property law. tt Robert Lee is an Associate with the firm Koo, Winkler, Hsu and Hwang in Taipei. ttt J.D. Expected, May 1994, UCLA School of Law.

COMMENTS RELEASING THE GRAYS: IN SUPPORT OF LEGALIZING PARALLEL IMPORTS Andrew Rufft I. INTRODUCTION Imagine for a moment, or fantasize if you wish, that you have come upon a large sum of money and have decided to spend it on a new imported luxury car. You tour the lots of various authorized importers-Lexis, BMW, Mercedes, and so on. You compare prices, models, and colors. Perhaps you have even decided on the car which is perfect for you, let's say a BMW seven series. Now a friend tells you that you have not really exhausted your options. You can buy a round-trip ticket to Germany, purchase your BMW there, pay for transport to the United States, customs duties and costs for conversion to U.S. emissions and safety standards and still save money, not to mention the free trip to Europe.l You won't be breaking the law-in fact, President Reagan referred to similar '2 im- ports by members of his administration as standard practice. Your friend has inspired you to do some creative thinking of your own. You recall that your neighbor, Fred, is also contemplat- ing purchasing a luxury import. If you bought two cars while in Europe, you could save Fred the cost of purchasing through an au- t J.D. expected 1994, UCLA School of Law. The initial research for this Com- ment was conducted in Taipei, Taiwan. My sincerest thanks to Robin Winkler, Gene Chao, and Mark Grady for their generous assistance and insightful comments. 1. Estimates range as to how much can be saved by importing cars independently depending on the model of car and the fluctuation of currency rates between markets. By 1985 estimates, consumers could knock $8000 off the price of certain Mercedes mod- els by purchasing them abroad and paying for conversion to U.S. standards. See Ed- ward Boyer, The Assault on the Right to Buy Cheap Imports, FORTUNE, Jan. 7, 1985, at 89. Elsewhere it has been found that foreign car purchasers can knock 25% off the price of some models by purchasing them from abroad and importing them into the United States. See Maks Westerman, The $7 Billion Gray Market: Where It Stops, No- body Knows, Bus. WK., Apr. 15, 1985, at 86. 2. Westerman, supra note 1, at 86.

The purpose of this study was to establish a normal database in children for one parameter of mobility, walking distance in 30 seconds. Also, we addressed the difference in distance walked by age and the contribution of several variables to the distance walked. Two hundred twenty-seven children between six and 13 years old were recruited from public schools in Iowa. Testing took place in standardized locations (eg, school gymnasiums) using standardized testing procedures. Distance walked in 30 seconds, age, height, right lower extremity length, weight, body type, gender, and race/ethnicity were recorded for each subject. Distance walked increased from six to eight years of age, plateaued from eight to 11 years, declined at 12 years, and increased at 13 years of age. Multiple linear regression identified leg length and weight as two variables explaining 14.4% of the variance in distance walked. The database provides a peer reference for use with children having suspected mobility limitations and is the beginning of a project to develop a Standard Task Measurement for Mobility.