Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.

Defunding preoperative histories and physical exams: putting the cart before the evidence?

OBJECTIVE: Several Canadian health authorities have defunded preoperative cataract history and physical examinations performed by general practitioners. While these authorities suggest that such decisions are evidence-based, we are unaware of reviews addressing this topic, nor have health authorities been forthcoming with evidence used in their decision-making processes. The objective of this study is to perform a comprehensive review of the literature regarding the value of preoperative histories and physical examinations in cataract surgery. DESIGN: Systematic review. METHODS: The following databases were searched: PubMed, MEDLINE, Cochrane Library, Google Scholar, Web of Science, EMBASE, CINAHL, and BIOSIS Previews. Only higher-level forms of evidence were assessed, including randomized controlled trials, cohort, and case-control studies. Two reviewers independently assessed titles and abstracts for concordance with inclusion criteria. Disagreements between authors were resolved by discussion. RESULTS: We identified 3 articles that met our inclusion criteria: two prospective and one retrospective cohort studies. These articles suggest traditional preoperative histories and physical examinations could be replaced by a health questionnaire (Jastrzebski et al. and Reeves et al.) or eliminated altogether (Alboim et al.). DISCUSSION: Scientific literature presently contains 3 studies suggesting that preoperative histories and physical examinations could be modified or eliminated. However, methodological weaknesses and data analysis derived from these studies suggests defunding preoperative medical examination may be premature. CONCLUSIONS: While finding efficiencies in medical care is admirable, physicians should be cautious in accepting recommendations that reduce checks ensuring perioperative safety. Further studies of better methodological quality should be completed to clarify the present evidence.

Disinfection of the Goldman applanation tonometer: a systematic review.

OBJECTIVES: The Goldmann applanation tonometer is the gold standard for measuring intraocular pressure and a possible vector for the transmission of infectious diseases. The purpose of this study is to consolidate the evidence pertaining to the disinfection of Goldmann tonometers in an effort to facilitate an informed discussion regarding public policy in this important area. DESIGN: Systematic review. METHODS: An exhaustive literature review was undertaken to identify primary-level research that assesses the effectiveness of different agents used in the disinfection of Goldmann applanation tonometer prisms. Seven discrete databases were reviewed by 2 independent researchers, and a symmetrical screening process was used to identify and review all pertinent studies. RESULTS: Our review identified only 19 primary-level studies that relate specifically to the disinfection of Goldmann tonometer prisms. These studies are largely heterogeneous with regard to the pathogens and disinfectants that were tested and the experimental protocols that were employed. Accordingly, definitive conclusions as to the optimal agent cannot be made on this basis. Furthermore, the results of our review reinforce previous suggestions that only adenovirus has been transmitted between patients via the Goldmann tonometer. CONCLUSIONS: The present state of the literature does not permit a definitive conclusion regarding optimal disinfection agent for Goldmann applanation tonometer prisms. Further well-constructed studies are required to better delineate the effectiveness of disinfectants in the specific context of tonometer prisms.

Glaucoma screening by primary care physicians in southern Alberta: patterns, methods and deficiencies.

BACKGROUND: This study was undertaken to determine the proportion of primary care physicians who routinely assess their patients for risk factors associated with glaucoma as well as the elements that underlie whether these physicians screen for glaucoma. METHODS: A brief, confidential questionnaire was distributed to primary care physicians on 3 occasions. The survey asked about the physicians' background, their glaucoma screening habits, reasons for not doing routine screening and measures that would help the physician begin to do screening. Responses were categorized and percentages calculated. RESULTS: Of the 161 questionnaires distributed, 49 (30.4%) were returned. Of the respondents, 53% claimed that they routinely screened for glaucoma; more urban than rural physicians did so (57% vs. 44%). Some of the screening methods documented were inappropriate. The reasons most often given for not screening were lack of equipment and skills, cited by 48% and 30%, respectively, of the physicians who claimed not to be currently screening. Most (85%) of the respondents who claimed to routinely screen for glaucoma said they would refer the patient to an ophthalmologist or optometrist if they suspected the condition. Among the measures that would help physicians currently not screening to begin doing so, training and access to equipment and facilities were most often suggested by those not currently screening as well as those routinely doing so. INTERPRETATION: If family physicians are an appropriate group to screen for glaucoma, and if mass screening for this condition is worth while, education and access to equipment are critical.