Fc-competent multispecific PDL-1/TIGIT/LAG-3 antibodies potentiate superior anti-tumor T cell response.

The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers.

A comparison of the effects of sudden gains and depression spikes on short- and long-term depressive symptoms in a randomized controlled trial of behavioral activation and cognitive behavioural therapy.

OBJECTIVE: The aim of this study was to examine the effects of sudden gains and depression spikes in a randomized controlled trial of cognitive behavioral therapy (CBT) and behavioral activation (BA) for depression (COBRA trial). METHOD: This is a secondary analysis of 300 adults with major depressive disorder (MDD) who received CBT (n = 156) or BA (n = 144) (Richards et al., 2016). The Patient Health Questionnaire (PHQ-9) and Structured Clinical Interview Schedule (SCID) were used to measure depression symptoms at 6-, 12-, and 18-month follow-up. RESULTS: One-hundred and ten (37%) individuals experienced sudden gains, and 77 (26%) experienced depression spikes. There were no differences in rates of gains or spikes between treatments. Individuals with sudden gains had lower PHQ-9 scores across follow-up and were less likely to meet SCID criteria than those without a sudden gain. Generalized estimating equation (GEE) models demonstrated that individuals who had a sudden gain and were in CBT had lower PHQ-9 scores at 6 and 18 months than those in BA. Conversely, individuals who had a depression spike and were in CBT had higher PHQ-9 scores across follow-up compared to those without a depression spike and also a greater chance of meeting SCID criteria for MDD at 18 months than those who received BA. CONCLUSIONS: The short- and long-term impact of discontinuous change varied by type of treatment package. Identifying strategies within treatment packages and client processes that are associated with gains and spikes may help to inform treatment planning and clinical decision-making. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Salmonellosis Outbreak After a Large-Scale Food Event in Virginia, 2017.

OBJECTIVES: The Virginia Department of Health (VDH) identified an outbreak of Salmonella serotype Javiana infections in Virginia after a chili and chowder cook-off with 11 competitors and about 2500 attendees on September 30, 2017. The objectives of this study were to assess the extent of the outbreak and identify the most likely source of exposure. METHODS: To identify people with suspected Salmonella infection, VDH used press releases and social media posts to recruit event attendees to take an online survey about foods eaten at the cook-off and any gastrointestinal (GI) symptoms experienced. VDH defined a case as reported GI illness that occurred within 1 week after eating food from the cook-off. Confirmed cases required a clinical specimen culture positive for Salmonella. Probable cases reported diarrhea or related clinical symptoms. "Not ill" people did not report GI illness. Investigators calculated unadjusted relative risks of illness and performed stratified analysis to address potential confounding. Available food samples were tested for Salmonella. Environmental health specialists interviewed food handlers and inspected restaurants where 3 competitors had prepared food. RESULTS: Of 438 survey responses, 171 (39%) met the case definition. Of all chilies and chowders consumed, Chowder A was associated with the highest relative risk of illness (8.9; 95% CI, 5.7-13.7). A Chowder A sample tested positive for Salmonella serotype Javiana. The environmental investigation did not identify an original contamination source but did find deficiencies in maintaining safe cooking temperatures. CONCLUSIONS: Epidemiologic and laboratory findings indicated that Chowder A was the most likely cause of outbreak. Recommendations to prevent future outbreaks include preparation of all food on-site to ensure safe temperatures during food preparation and service.

Trajectories of Change in a Group Behavioral Activation Treatment for Severe, Recurrent Depression.

Depression is a common and costly problem. Behavioral Activation (BA) is an effective treatment for depression when delivered 1:1, but group treatments often do not perform as well as 1:1 treatments. One way to begin to understand how group treatments perform is to assess the process of change during treatment. This study examined trajectories of change across 10-session group BA for individuals with severe, chronic, or recurrent forms of depression. We also tested whether individuals who had associated sudden gains or depression spikes had better outcomes than those who did not have these change patterns. We examined psychological and sociodemographic predictors of the patterns of change. Participants were 104 individuals who met diagnostic criteria for major depressive disorder and participated in one of 10 BA groups, provided over a 2-year period. A linear, but not quadratic or cubic, rate of change fit the data and the effect size for the change in mood symptoms from baseline to posttreatment was large, Cohen's d = 1.25. Although 34% (26 of the 77 who provided outcome data) of individuals had a sudden gain and 10% (7/77) had a depression spike, neither sudden gains nor depression spikes predicted posttreatment outcomes. None of the demographic or psychological factors (rumination, behavioral activation) predicted the pattern of change. These results suggest that although group BA may help to reduce depressive symptoms in individuals with severe, recurrent, and/or chronic forms of depression, the overall linear pattern of change is different from quadratic patterns of change reported for 1:1 BA.

Are ball pits located in physical therapy clinical settings a source of pathogenic microorganisms?

Clinical, therapeutic ball pits commonly used by physical therapists to provide sensory stimulation to children were investigated for microbial colonization. Due to the permissive and hospitable environment provided by these ball pits, microorganisms can accumulate to levels that increase the ease of transmission toexposed individuals. Our study found considerable microbial colonization in ball pits located in clinical settings, including 8 opportunistic pathogenic bacteria and 1 opportunistic pathogenic yeast.

Incremental Hospital Cost and Length-of-Stay Associated With Treating Adverse Events Among Medicare Beneficiaries Undergoing Lumbar Spinal Fusion During Fiscal Year 2013.

STUDY DESIGN: A retrospective study. OBJECTIVES: To report the incremental hospital resource consumption associated with treating selected adverse events experienced by Medicare beneficiaries undergoing a two- or three-level lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: Hospitals are increasingly at financial risk for the incremental resources consumed in treating patients experiencing adverse events because of public and private third-party payers' efforts to base hospital reimbursement on "pay for performance" measures. However, little is known about average incremental resources consumed in treating patients experiencing adverse events following lumbar spinal fusions. METHODS: The 2013 fiscal year Medicare Provider Analysis and Review file was used to identify 83,658 Medicare beneficiaries who underwent two- or three vertebrae-level lumbar spinal fusion. International Classification of Diseases-9th-Clinical Modification diagnostic and procedure codes were used to identify the frequencies of nine adverse events. This study estimated both the observed and risk-adjusted incremental hospital resources consumed (cost and length of stay [LOS]) in treating Medicare beneficiaries experiencing each adverse event. RESULTS: Overall, 17.7% of Medicare beneficiaries undergoing lumbar spinal fusion experienced at least one of the study's adverse events. Medicare beneficiaries experiencing any complication consumed significantly more hospital resources (incremental cost of $8911) and had longer LOS (incremental stays of 5.7 days). After adjusting for patient demographics and comorbid conditions, incremental cost of treating adverse events ranged from a high of $32,049 (infection) to a low of $9976 (transfusion). CONCLUSION: Adverse events frequently occur and add substantially to the hospital resource costs of patients undergoing spinal fusion. Shared decision-making instruments should clearly provide these risk estimates to the patient before surgical consideration. Investment in activities that have been shown to reduce specific adverse events is warranted, and this project may allow health systems to prioritize performance improvement areas. LEVEL OF EVIDENCE: 3.

The Incremental Hospital Cost and Length-of-Stay Associated With Treating Adverse Events Among Medicare Beneficiaries Undergoing THA During Fiscal Year 2013.

This paper estimates the incremental hospital resource consumption associated with treating selected adverse events experienced by Medicare beneficiaries (MBs) undergoing total hip arthroplasty (THA). This retrospective study, using the Medicare Provider Analysis and Review file, identified 174,167 MBs who underwent THA in 2013. Overall, 20.16% of MB undergoing THA experienced at least one adverse event. MB experiencing any adverse event consumed significantly higher hospital cost ($3429) and had longer length of stays (1.0 day). The risk-adjusted incremental cost of treating adverse events ranged from a high of $27,116 (pneumonia) to a low of $2626 (hemorrhage or post-operative shock requiring transfusion). Most major adverse events occurred infrequently, however when adverse events occurred, they add substantially to the hospital resource costs of treating MB.

The incremental hospital cost and length-of-stay associated with treating adverse events among Medicare beneficiaries undergoing TKA.

This paper estimates the incremental hospital resource consumption associated with treating selected adverse events experienced by Medicare beneficiaries undergoing TKA. This retrospective study, using the Medicare Provider Analysis and Review file, identified 353,650 Medicare beneficiaries who underwent a primary TKA during 2011. Overall, 11.82% of Medicare beneficiaries (MBs) undergoing TKA experienced at least one of the study's adverse events. MBs experiencing any adverse event consumed significantly more unadjusted hospital resources ($3110 cost) and had longer stays (1.3 days). The risk-adjusting incremental cost of treating adverse events ranged between $30,902 (pneumonia) and $2167 (hemorrhage or post-operative shock requiring transfusion). Most major adverse events occur infrequently; however when an adverse event occurs following TKA, it adds substantially to hospital costs.

The interplay of plant and animal disease in a changing landscape: the role of sudden aspen decline in moderating Sin Nombre virus prevalence in natural deer mouse populations.

We examined how climate-mediated forest dieback regulates zoonotic disease prevalence using the relationship between sudden aspen decline (SAD) and Sin Nombre virus (SNV) as a model system. We compared understory plant community structure, small mammal community composition, and SNV prevalence on 12 study sites within aspen forests experiencing levels of SAD ranging from <10.0% crown fade to >95.0% crown fade. Our results show that sites with the highest levels of SAD had reduced canopy cover, stand density, and basal area, and these differences were reflected by reductions in understory vegetation cover. Conversely, sites with the highest levels of SAD had greater understory standing biomass, suggesting that vegetation on these sites was highly clustered. Changes in forest and understory vegetation structure likely resulted in shifts in small mammal community composition across the SAD gradient, as we found reduced species diversity and higher densities of deer mice, the primary host for SNV, on sites with the highest levels of SAD. Sites with the highest levels of SAD also had significantly greater SNV prevalence compared to sites with lower levels of SAD, which is likely a result of their abundance of deer mice. Collectively, results of our research provide strong evidence to show SAD has considerable impacts on vegetation community structure, small mammal density and biodiversity and the prevalence of SNV.