Summary Unacceptable levels of Mycobacterium tuberculosis transmission are noted in high burden settings and a renewed focus on reducing person-to-person transmission in these communities is needed. ...We review recent developments in the understanding of airborne transmission. We outline approaches to measure transmission in populations and trials and describe the Wells–Riley equation, which is used to estimate transmission risk in indoor spaces. Present research priorities include the identification of effective strategies for tuberculosis infection control, improved understanding of where transmission occurs and the transmissibility of drug-resistant strains, and estimates of the effect of HIV and antiretroviral therapy on transmission dynamics. When research is planned and interventions are designed to interrupt transmission, resource constraints that are common in high burden settings—including shortages of health-care workers—must be considered.
Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences ...between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.
The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human ...cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8
+
T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.
Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) ...naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1–based ICBs.
We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated.
Eighty-six patients were included in the analysis; the median age was 63 years (range 33–84) and the median number of prior therapies was 2 (range 1–10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval CI = 26–47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3–8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41–66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%).
Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.
•Retrospective analysis of 86 patients receiving cabozantinib after immunotherapy.•Sixty-four percent received immunotherapy alone and 29% received in combination with vascular endothelial growth factors.•The overall response rate was 36% (95% confidence interval = 26–47%); the median overall survival was 13 months.•The toxicity profile was similar to what was reported in the METEOR trial.•Cabozantinib is active after immunotherapy with no new safety signals.
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is ...not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to β-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended. This review will focus on pharmacogenetics and pharmacogenomics and their role in reducing ADRs, especially those caused by drug hypersensitivity reactions.
More effective treatments are needed for human papilloma virus (HPV)-induced cancers despite HPV virus vaccination. The oncogenic HPV protein targets are currently undruggable and intracellular and ...therefore there are no antibodies to these targets. Here we report the discovery of TCR mimic monoclonal antibodies (TCRm mAb) specific for the HPV E7 protein p11-19, YMLDLQPET, when presented on the cell surface in the context of HLA-A*02:01 by use of human phage display libraries. One of the mAbs, 3F8, was able to specifically mediate T cell- redirected cytotoxicity, in a bispecific T cell engager (BiTE) form. While further studies are required to assess the therapeutic potential of this approach, the study provided the proof of concept that TCRm mAb could be a therapeutic strategy for HPV-induced human cancers.
Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is ...crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multicentre studies are necessary to determine indications and establish common testing protocols.
•First assessment of vaccine-related advertisements on Facebook Ad Archive.•Top pro-vaccine ad themes: vaccine promotion, philanthropy, news.•Top anti-vaccine ad themes: vaccine harm, promoting ...choice, uncovering “fraud”.•Two buyers accounted for majority (54%) of anti-vaccine advertising content.•Facebook policies negatively impact first time ad buyers, largely pro-vaccine.
In 2018, Facebook introduced Ad Archive as a platform to improve transparency in advertisements related to politics and “issues of national importance.” Vaccine-related Facebook advertising is publicly available for the first time. After measles outbreaks in the US brought renewed attention to the possible role of Facebook advertising in the spread of vaccine-related misinformation, Facebook announced steps to limit vaccine-related misinformation. This study serves as a baseline of advertising before new policies went into effect.
Using the keyword ‘vaccine’, we searched Ad Archive on December 13, 2018 and again on February 22, 2019. We exported data for 505 advertisements. A team of annotators sorted advertisements by content: pro-vaccine, anti-vaccine, not relevant. We also conducted a thematic analysis of major advertising themes. We ran Mann-Whitney U tests to compare ad performance metrics.
309 advertisements were included in analysis with 163 (53%) pro-vaccine advertisements and 145 (47%) anti-vaccine advertisements. Despite a similar number of advertisements, the median number of ads per buyer was significantly higher for anti-vaccine ads. First time buyers are less likely to complete disclosure information and risk ad removal. Thematically, anti-vaccine advertising messages are relatively uniform and emphasize vaccine harms (55%). In contrast, pro-vaccine advertisements come from a diverse set of buyers (83 unique) with varied goals including promoting vaccination (49%), vaccine related philanthropy (15%), and vaccine related policy (14%).
A small set of anti-vaccine advertisement buyers have leveraged Facebook advertisements to reach targeted audiences. By deeming all vaccine-related content an issue of “national importance,” Facebook has further the politicized vaccines. The implementation of a blanket disclosure policy also limits which ads can successfully run on Facebook. Improving transparency and limiting misinformation should not be separate goals. Public health communication efforts should consider the potential impact on Facebook users’ vaccine attitudes and behaviors.
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