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Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0–1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786. Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4–11·9] vs 9·2 months [5·9–11·2]; stratified hazard ratio 0·78 [0·63–0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3–29·4) with atezolizumab compared with 12% (6·7–18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3–4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.

At-home rapid COVID-19 tests in the U.S. utilize nasal-swab specimens and require high viral loads to reliably give positive results. Longitudinal studies from the onset of infection have found infectious virus can present in oral specimens days before nasal. Detection and initiation of infection-control practices may therefore be delayed when nasal-swab rapid tests are used, resulting in greater transmission to contacts. We assessed whether index cases first identified by rapid nasal-swab COVID-19 tests had more transmission to household contacts than index cases who used other test types (tests with higher analytical sensitivity and/or non-nasal specimen types). In this observational cohort study, 370 individuals from 85 households with a recent COVID-19 case were screened at least daily by RT-qPCR on one or more self-collected upper-respiratory specimen types. A two-level random intercept model was used to assess the association between the infection outcome of household contacts and each covariable (household size, race/ethnicity, age, vaccination status, viral variant, infection-control practices, and whether a rapid nasal-swab test was used to initially identify the household index case). Transmission was quantified by adjusted secondary attack rates (aSAR) and adjusted odds ratios (aOR). An aSAR of 53.6% (95% CI 38.8–68.3%) was observed among households where the index case first tested positive by a rapid nasal-swab COVID-19 test, which was significantly higher than the aSAR for households where the index case utilized another test type (27.2% 95% CI 19.5–35.0%, P = 0.003 pairwise comparisons of predictive margins). We observed an aOR of 4.90 (95% CI 1.65–14.56) for transmission to household contacts when a nasal-swab rapid test was used to identify the index case, compared to other test types. Use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may be less effective at limiting transmission to household contacts than other test types.

Over the past several decades, Law & Economics has established itself as one of the most well-known branches of interdisciplinary legal scholarship. The tools of L&E have been applied to a wide range of legal issues and have even been brought to bear on Critical Race Theory in an attempt to address some of CRT’s perceived shortcomings. This Article seeks to reverse this dynamic of influence by applying CRT and related critical perspectives to the field of economics. We call our approach Abolition Economics. By embracing the abolitionist ethos of “dismantle, change, and build,” we seek to break strict disciplinary habits of modelling and identification, destabilize value systems implicit in mainstream economics, model society more fully as made up of interconnected humans, and develop a richer and more realistic understanding of racialized economic inequality, hierarchy, and oppression. We argue that, contrary to accepted disciplinary conventions, such an endeavor does not introduce new (inappropriate) ideological content into (objective) economics; rather, this endeavor is necessary to fully reveal the ideological content already embedded in mainstream economics as it is currently practiced, and the consequences of that embedding in supporting the functioning of systems of racial capitalism and racial injustice. We believe that imagining the possibility of a different economics—an Abolition Economics—can be an act not only of resistance but, crucially, of freedom-making.

Acid orange 74 (AO74) is a chromium-complex monoazo acid dye widely used in the textile industry. Due to being highly toxic and non-biodegradable, it must be removed from polluted water to protect the health of people and the environment. The aim of this study was two-fold: to evaluate the biosorption of AO74 from an aqueous solution by utilizing HCl-pretreated Lemna sp. (HPL), and to examine dye desorption from the plant material. The maximum capacity of AO74 biosorption (64.24 mg g-1) was reached after 4 h at the most adequate pH, which was 2. The biosorption capacity decreased 25% (to 48.18 mg g-1) during the second biosorption/desorption cycle and remained essentially unchanged during the third cycle. The pseudo-second-order kinetics model concurred well with the experimental results of assays involving various levels of pH in the eluent solution and distinct initial concentrations of AO74. NaOH (0.01 M) was the best eluent solution. The Toth isotherm model best described AO74 biosorption equilibrium data. FTIR analysis confirmed the crucial role of HPL proteins in AO74 biosorption. SEM-EDX and CLSM techniques verified the effective biosorption/desorption of the dye during the three cycles. Therefore, HPL has potential for the removal of AO74 dye from wastewaters.

Geographic variation in the vocal behavior of manatees has been reported but is largely unexplored. Vocalizations of wild West Indian manatees ( Trichechus manatus ) were recorded with hydrophones in Florida from Florida manatees ( Trichechus manatus latirostris ), and in Belize and Panama from Antillean manatees ( Trichechus manatus manatus ) to determine if calls varied between subspecies and geographic regions. Calls were visually classified into five categories: squeaks, high squeaks, squeals, squeak-squeals, and chirps. From these five categories, only three call types (squeaks, high squeaks and squeals) were observed in all three populations. Six parameters from the temporal and frequency domains were measured from the fundamental frequency of 2878 manatee vocalizations. A repeated measures PERMANOVA found significant differences for squeaks and high squeaks between each geographic location and for squeals between Belize and Florida. Almost all measured frequency and temporal parameters of manatee vocalizations differed between and within subspecies. Variables that may have influenced the variation observed may be related to sex, body size, habitat and/or other factors. Our findings provide critical information of manatee calls for wildlife monitoring and highlight the need for further study of the vocal behavior of manatees throughout their range.

Despite national guidelines promoting hepatitis C virus (HCV) testing in prisons, there is substantial heterogeneity on the implementation of HCV testing in jails. We sought to better understand barriers and opportunities for HCV testing by interviewing a broad group of stakeholders involved in HCV testing and treatment policies and procedures in Massachusetts jails. We conducted semi-structured interviews with people incarcerated in Middlesex County Jail (North Billerica, MA), clinicians working in jail and community settings, corrections administrators, and representatives from public health, government, and industry between November 2018-April 2019. 51/120 (42%) of people agreed to be interviewed including 21 incarcerated men (mean age 32 [IQR 25, 39], 60% non-White). Themes that emerged from these interviews included gaps in knowledge about HCV testing and treatment opportunities in jail, the impact of captivity and transience, and interest in improving linkage to HCV care after release. Many stakeholders discussed stigma around HCV infection as a factor in reluctance to provide HCV testing or treatment in the jail setting. Some stakeholders expressed that stigma often led decisionmakers to estimate a lower \"worth\" of incarcerated individuals living with HCV and therefore to decide against paying for HCV testing.\". All stakeholders agreed that HCV in the jail setting is a public health issue that needs to be addressed. Exploring stakeholders' many ideas about how HCV testing and treatment can be approached is the first step in developing feasible and acceptable strategies.

AbstractIntroductionSepsis identification and treatment is a priority for emergency department (ED) providers and payors alike. However, aggressive metrics aimed at improving sepsis care could have unintended consequences for patients who do not have sepsis. MethodsAll ED patient visits for a one month period before and after a quality initiative to increase early antibiotic use in septic patients were included. Overall broad spectrum (BS) antibiotic use, admission rates, and mortality were compared in the 2 time periods. A more detailed chart review was performed on those who received BS antibiotics in the before and after cohorts. Patient were excluded for pregnancy, age < 18, COVID-19 infection, hospice patients, left ED against medical advice, and if antibiotics were given for prophylaxis. In BS antibiotic treated patients, we sought to determine mortality, rates of subsequent multidrug resistant (MDR) or Clostridium Difficile (CDiff) infections and rates of non-infected patients receiving BS antibiotics. ResultsThere were 7967 and 7407 ED visits in the pre- and post-implementation periods, respectively. Of those, BS antibiotics were administered in a total of 3.9% pre-implementation and 6.2% post-implementation ( p ≤ 0.00001). Admission was more common in the post-implementation period, but overall mortality was unchanged (0.9% pre-implementation and 0.8% post-implementation, p = 0.41). After exclusions, 654 patients treated with BS antibiotics were included in the secondary analyses. Baseline characteristics were similar between the pre-implementation and post-implementation cohorts. There was no difference in the rate of CDiff infection or the proportion of patients receiving BS antibiotics who were not infected, but there was an increase in the post-implementation period in MDR infections after ED BS antibiotics, 0.72% vs. 0.35% of the entire ED cohorts, p = 0.0009. ConclusionsWe found that a QI sepsis initiative was associated with an increase in the proportion of patients who received BS antibiotics in the ED, and a small absolute increase in associated subsequent MDR infections, with no apparent effect on mortality in all ED patients or the subset treated with BS antibiotics. Further research is needed to assess the impact on all patients affected by aggressive sepsis protocols and initiatives, rather than only those with sepsis.

Bacterial diseases cause high mortality in Penaeus (Litopenaeus) vannamei postlarvae. Therefore, appropriate application of efficient therapeutic products is of vital importance for disease control. This study evaluated through in vitro analyses the antimicrobial effectiveness of commercial therapeutic products used for P. vannamei bacterial diseases and antibiotics against pathogenic Vibrio strains circulating in Ecuadorian hatcheries. Twenty strains were isolated from 31 larvae samples with high bacterial counts from 10 hatcheries collected during mortality events. The strains virulence was verified through challenge tests with Artemia franciscana nauplii and P. vannamei postlarvae. Through 16S rRNA sequence analysis, strains showed a great similarity to the Vibrio sequences reported as pathogens, with 95% belonging to the Harveyi clade. Through antibiograms and minimal inhibitory concentration (MIC) in vitro tests we found that furazolidone, ciprofloxacin, chloramphenicol, norfloxacin, nalidixic acid, florfenicol, fosfomycin and enrofloxacin inhibited the growth of all or most of the strains. Less efficient antibiotics were penicillin, oxytetracycline and tetracycline. A multiple antibiotic resistance (MAR) index of 0.23 showed some level of resistance to antibiotics, with two MAR prevalent patterns (Penicillin-Oxytetracycline and Penicillin-Oxytetracycline-Tetracycline). From a total of 16 natural products (five probiotics, nine organic acids and two essential oils), only three (one probiotic, one organic acid and one essential oil) were effective to control most of the strains. Shrimp producers can apply relatively simple in vitro analyses, such as those employed in this study, to help take adequate management decisions to reduce the impact of bacterial diseases and increase profit.

Intractable penile pain can be a very difficult condition to address. Studies have shown that both locally advanced and metastatic penile cancer, along with its associated management options and subsequent complications, yield a very poor prognosis, with pain being the most feared symptom. Furthermore, a lack of palliative therapy has been demonstrated in this patient population, with an emphasis on the need for implementing future options. This case depicts a 67-year-old male, with a past medical history of metastatic prostate cancer involving the penis, who presented with intractable penile pain. To the authors' knowledge, this will be the first documented case of the successful utilization of a bilateral superior hypogastric plexus neurolysis in the management of intractable neoplasm-related penile pain attributed to both radiation-induced injury in the treatment of malignant neoplasm and penile pain secondary to metastatic prostate cancer to the penis. As a currently under-utilized treatment option in the management of intractable neoplasm-related penile pain, this case presentation acts to increase awareness of its potential use, therefore reducing the need for analgesics and the associated burdens, as well as improving patient palliation. Furthermore, this case offers evidence supporting the encouragement of its use in the general management of intractable penile pain due to other pathophysiology.

BackgroundOvercoming the suppressive tumor microenvironment (TME) remains an important unmet challenge for chimeric antigen receptor (CAR) T cell therapies. A key suppressive factor, transforming growth factor β (TGF-β), is a primary driver of T cell suppression reducing T cell receptor (TCR)-mediated cytotoxicity and driving the differentiation of immunosuppressive regulatory T cells (Tregs) in the TME.MethodsTo overcome TGF-β-specific immunosuppression, we employed a TGF-β-targeting CAR co-expressed in T cells with a human papillomavirus type 16 (HPV16) E711-19-specific, HLA-A*02:01-restricted TCR (E7 TCR).ResultsIn comparison to T cells expressing E7 TCR alone or E7 TCR with an irrelevant CD19-targeting CAR, T cells co-transduced with E7 TCR and TGF-β CAR showed enhanced proliferation and cytokine production, while maintained cytotoxicity throughout repeat antigen challenge assays with HPV16+ Ca Ski tumor cells. The inclusion of TGF-β CAR also reduced PD1+ expression and Treg differentiation after repeat antigen challenges. Transcriptional analysis further confirmed reduced FOXP3 expression as well as enhanced proinflammatory genes such as TNF and IFNG.ConclusionsIn combination, these data clearly show that a TGF-β CAR can enhance TCR function and limit Treg differentiation and is therefore likely to improve the function and persistence of TCR therapies in the TME.