The Food and Drug Administration\u27s Evolving Regulation of Press Releases: Limits and Challenges

The Food and Drug Administration (FDA) has developed an informal framework for regulating press releases by drug and medical device companies. FDA asserted jurisdiction over press releases based on its authority over labeling and advertising, and over the past 20 years, the agency has both broadened and scaled back its claims to authority over press statements. Despite a somewhat predictable framework for anticipating how FDA regulates press materials, the agency\u27s approach appears to be in flux. FDA will not tolerate false or misleading statements in press materials, but there are legal and practical limits to its regulation in this area. The agency has had to adjust its approach to account for First Amendment concerns and resource limitations, which has led FDA to cooperate with the Securities and Exchange Commission (SEC), and take more creative responses to allegedly violative press materials. This article discusses how FDA has regulated press materials in the past, and how recent developments may signal new directions in the agency\u27s regulatory approach. The article proposes a framework for evaluating whether FDA might assert jurisdiction, and what the rules are if it does. The article considers the legal theories behind FDA\u27s approach and the implications for manufacturers

B Cells Regulate Neutrophilia during Mycobacterium tuberculosis Infection and BCG Vaccination by Modulating the Interleukin-17 Response

We have previously demonstrated that B cells can shape the immune response to Mycobacterium tuberculosis, including the level of neutrophil infiltration and granulomatous inflammation at the site of infection. The present study examined the mechanisms by which B cells regulate the host neutrophilic response upon exposure to mycobacteria and how neutrophilia may influence vaccine efficacy. To address these questions, a murine aerosol infection tuberculosis (TB) model and an intradermal (ID) ear BCG immunization mouse model, involving both the μMT strain and B cell-depleted C57BL/6 mice, were used. IL (interleukin)-17 neutralization and neutrophil depletion experiments using these systems provide evidence that B cells can regulate neutrophilia by modulating the IL-17 response during M. tuberculosis infection and BCG immunization. Exuberant neutrophilia at the site of immunization in B cell-deficient mice adversely affects dendritic cell (DC) migration to the draining lymph nodes and attenuates the development of the vaccine-induced Th1 response. The results suggest that B cells are required for the development of optimal protective anti-TB immunity upon BCG vaccination by regulating the IL-17/neutrophilic response. Administration of sera derived from M. tuberculosis-infected C57BL/6 wild-type mice reverses the lung neutrophilia phenotype in tuberculous μMT mice. Together, these observations provide insight into the mechanisms by which B cells and humoral immunity modulate vaccine-induced Th1 response and regulate neutrophila during M. tuberculosis infection and BCG immunization. © 2013 Kozakiewicz et al

Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.

Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes

Perceived Discrimination and Self-Reported Quality of Care Among Latinos in the United States

Given the persistence of health and health-care disparities among Latinos in the United States and evidence that discrimination affects health and health care, an investigation of the relationship between perceived discrimination and quality of health care among Latinos is warranted. To examine the relationship of perceived discrimination (in general and in regard to doctors and medical personnel) with self-reported quality of health care and doctor-patient communication in a nationally representative Latino population sample. Participants were 1,067 Latino adults aged ≥18 years living in the US selected via random-digit dialing. Telephone interviews were conducted in 2008 during Wave 2 of the Pew Hispanic Center/Robert Wood Johnson Foundation Hispanic Healthcare Survey. US-born Latinos were twice as likely to report general discrimination as foreign born: 0.32 SD versus −0.23 SD (P < 0.001) on the Detroit Area Survey (DAS) discrimination scale. Higher DAS discrimination was associated with lower self-reported quality of care in US-born Latinos [OR = 0.5; 95% CI (0.3, 0.9); P = 0.009]. For foreign-born Latinos, report of any doctor or medical staff discrimination was associated with lower quality of care [OR = 0.5; 95% CI (0.3, 0.9); P = 0.03], but the DAS was not. For US-born Latinos, doctor discrimination and higher DAS were jointly associated with worse doctor-patient communication. For foreign-born Latinos, the effect of discrimination on doctor-patient communication was significantly smaller than that observed in US-born Latinos. Given the association between perceived discrimination and quality of care, strategies to address discrimination in health-care settings may lead to improved patient satisfaction with care and possibly to improved treatment outcomes

Myosin-I nomenclature

We suggest that the vertebrate myosin-I field adopt a common nomenclature system based on the names adopted by the Human Genome Organization (HUGO). At present, the myosin-I nomenclature is very confusing; not only are several systems in use, but several different genes have been given the same name. Despite their faults, we believe that the names adopted by the HUGO nomenclature group for genome annotation are the best compromise, and we recommend universal adoption

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

AbstractBackgroundFor patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering 90Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.MethodsFifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N=29, 90Y-clivatuzumab tetraxetan, weekly 6.5mCi/m2doses×3, plus gemcitabine, weekly 200mg/m2 doses×4 starting 1week earlier) or Arm B (N=29, 90Y-clivatuzumab tetraxetan alone, weekly 6.5mCi/m2doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.ResultsCytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1year.ConclusionsClinical studies of 90Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting

Sense of Coherence and Gambling: Exploring the Relationship Between Sense of Coherence, Gambling Behaviour and Gambling-Related Harm

Understanding why some people experience problems with gambling whilst others are able to restrict gambling to recreational levels is still largely unexplained. One potential explanation is through salutogenesis, which is a health promotion approach of understanding factors which move people towards health rather than disease. An important aspect of salutogenesis is sense of coherence. Individuals with stronger sense of coherence perceive their environment as comprehensible, manageable and meaningful. The present study examined the relationship of individuals’ sense of coherence on their gambling behaviour and experience of gambling related harm. This exploratory study utilised an archival dataset (n = 1236) from an online, cross sectional survey of people who had experienced negative consequences from gambling. In general, a stronger sense of coherence was related to lower problem gambling severity. When gambling behaviour was controlled for, sense of coherence was significantly related to the experience of individual gambling harms. A strong sense of coherence can be seen as a protective factor against problematic gambling behaviour, and subsequent gambling related harms. These findings support the value of both primary and tertiary prevention strategies that strengthen sense of coherence as a harm minimisation strategy. The present study demonstrates the potential value of, and provides clear direction for, considering sense of coherence in order to understand gambling-related issues.This study was funded by the Victorian Responsible Gambling Foundation, Grant VRGF1-13

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Observation of electroweak production of two jets in association with an isolated photon and missing transverse momentum, and search for a Higgs boson decaying into invisible particles at 13 TeV with the ATLAS detector

This paper presents the measurement of the electroweak production of two jets in association with a $Z\gamma$ pair with the $Z$ boson decaying into two neutrinos. It also presents the search for invisible or partially invisible decays of a Higgs boson with a mass of 125 GeV produced through vector-boson fusion with a photon in the final state. These results use data from LHC proton-proton collisions at $\sqrt{s}$ = 13 TeV collected with the ATLAS detector corresponding to an integrated luminosity of 139 fb$^{-1}$. The event signature, shared by all benchmark processes considered for measurements and searches, is characterized by a significant amount of unbalanced transverse momentum and a photon in the final state, in addition to a pair of forward jets. For electroweak production of $Z\gamma$ in association with two jets, the background-only hypothesis is rejected with an observed (expected) significance of 5.2 (5.1) standard deviations. The measured fiducial cross-section for this process is 1.31$\pm$0.29 fb. Observed (expected) upper limit of 0.37 (0.34) at 95% confidence level is set on the branching ratio of a 125 GeV Higgs boson to invisible particles, assuming the Standard Model production cross-section. The signature is also interpreted in the context of decays of a Higgs boson to a photon and a dark photon. An observed (expected) 95% CL upper limit on the branching ratio for this decay is set at 0.018 (0.017), assuming the 125 GeV Standard Model Higgs boson production cross-section

The ATLAS inner detector trigger performance in pp collisions at 13 TeV during LHC Run 2

The design and performance of the inner detector trigger for the high level trigger of the ATLAS experiment at the Large Hadron Collider during the 2016-18 data taking period is discussed. In 2016, 2017, and 2018 the ATLAS detector recorded 35.6 fb$^{-1}$, 46.9 fb$^{-1}$, and 60.6 fb$^{-1}$ respectively of proton-proton collision data at a centre-of-mass energy of 13 TeV. In order to deal with the very high interaction multiplicities per bunch crossing expected with the 13 TeV collisions the inner detector trigger was redesigned during the long shutdown of the Large Hadron Collider from 2013 until 2015. An overview of these developments is provided and the performance of the tracking in the trigger for the muon, electron, tau and $b$-jet signatures is discussed. The high performance of the inner detector trigger with these extreme interaction multiplicities demonstrates how the inner detector tracking continues to lie at the heart of the trigger performance and is essential in enabling the ATLAS physics programme