Bedrock morphology influences rock barrens turtle nesting habitat energy dynamics.

Energy absorption and flow through a nest is an important aspect of embryonic development in many reptile species including turtles. To date, few studies have explicitly attempted to quantify the energy flow through turtle nests, opting instead for the simplified approach offered by temperature index models. However, the quantification of the energy can provide an explicit abiotic link that can link biological models to biometeorological and ecohydrological processes and models. We investigated the energy flow through turtle nests occupying different bedrock morphologies within a Canadian Shield Rock Barren landscape, in Ontario, Canada. The taxons studied were Spotted Turtle (Clemmys guttata), Midland Painted Turtle (Chrysemys picta marginata), and Blanding's Turtle (Emydoidea blandingii). Nest temperature and soil moisture were measured in 2018 and 2019 using sensors placed in the soil adjacent to 12 turtle nest cavities. Three main rock morphologies were identified for each nest location, Crevice, Ledge, and Flat types, that are in order of decreasing bedrock percentage contact with the nest site. Ground heat flux and change in heat storage were determined using the calorimetric method for each nest, while the direction of energy flux between the atmosphere and the underlying rock was also determined. The Crevice nest morphology experienced the lowest ground heat flux on average (1.56 × 10-1 W m-2) and lowest cumulative heat storage (230 MJ) compared to the Flat (440 MJ) and Ledge (331 MJ) nests. However, over the diurnal cycle, large heat gains by Flat nests were mostly balanced out by nighttime heat losses. While Crevice nests saw the lowest daily heat storage gains, they experienced much lower heat losses over the evening period compared to the other nest types. Furthermore, we found that 59% of the energy is directed from the underlying bedrock into the Crevice nest, highlighting the importance of the bedrock in controlling thermal dynamics in the turtle nesting habitat. The lower variability in energy parameters for Crevice nest types can be attributed to higher amounts of nest-to-bedrock contact, compared to the flat nest types. Our results indicate that Crevice morphology may be ideal for turtles nesting at their northern limits because minimal heat loss during the evening can result in a more stable thermal incubation environment. Future conservation and habitat restoration efforts should consider the importance of bedrock morphology and prioritize the protection of Crevice nest sites. Furthermore, this work highlights important opportunities for potential interdisciplinary work between ecologists, climatologists, biologists, and hydrologists, specifically the integration of ecohydrological and biological models. This work also underscores the potential uncertainty of climate change impacts on turtle egg hatching success and nest sex ratios.

Interplay between B7-H3 and HLA class I in the clinical course of pancreatic ductal adenocarcinoma.

Human leukocyte antigen (HLA) class I defects are associated with cancer progression. However, their prognostic significance is controversial and may be modulated by immune checkpoints. Here, we investigated whether the checkpoint B7-H3 modulates the relationship between HLA class I and pancreatic ductal adenocarcinoma (PDAC) prognosis. PDAC tumors were analyzed for the expression of B7-H3, HLA class I, HLA class II molecules, and for the presence of tumor-infiltrating immune cells. We observed defective HLA class I and HLA class II expressions in 75% and 59% of PDAC samples, respectively. HLA class I and B7-H3 expression were positively related at mRNA and protein level, potentially because of shared regulation by RELA, a sub-unit of NF-kB. High B7-H3 expression and low CD8+ T cell density were indicators of poor survival, while HLA class I was not. Defective HLA class I expression was associated with unfavorable survival only in patients with low B7-H3 expression. Favorable survival was observed only when HLA class I expression was high and B7-H3 expression low. Our results provide the rationale for targeting B7-H3 in patients with PDAC tumors displaying high HLA class I levels.

Evidence-based clinical practice guideline for the pharmacologic management of acute dental pain in adolescents, adults, and older adults: A report from the American Dental Association Science and Research Institute, the University of Pittsburgh, and the University of Pennsylvania.

BACKGROUND: A panel convened by the American Dental Association Science and Research Institute, the University of Pittsburgh, and the University of Pennsylvania conducted systematic reviews and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after simple and surgical tooth extraction(s) and for the temporary management (ie, definitive dental treatment not immediately available) of toothache associated with pulp and periapical diseases in adolescents, adults, and older adults. TYPES OF STUDIES REVIEWED: The panel conducted 4 systematic reviews to determine the effect of opioid and nonopioid analgesics, local anesthetics, corticosteroids, and topical anesthetics on acute dental pain. The panel used the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations, Assessment, Development and Evaluation Evidence-to-Decision Framework to formulate recommendations. RESULTS: The panel formulated recommendations and good practice statements using the best available evidence. There is a beneficial net balance favoring the use of nonopioid medications compared with opioid medications. In particular, nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen likely provide superior pain relief with a more favorable safety profile than opioids. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications are first-line therapy for managing acute dental pain after tooth extraction(s) and the temporary management of toothache. The use of opioids should be reserved for clinical situations when the first-line therapy is insufficient to reduce pain or there is contraindication of nonsteroidal anti-inflammatory drugs. Clinicians should avoid the routine use of just-in-case prescribing of opioids and should exert extreme caution when prescribing opioids to adolescents and young adults.

Longitudinal study of stream ecology pre- and post- dam removal: Physical, chemical, and biological changes to a northern Michigan stream.

Over the past two decades, dam removal has become an increasingly important aspect of aquatic ecology. As a result of this work, ecological studies have arisen that monitor the changes to riverine ecosystems as a result of removal. Unfortunately, given the uncertain nature of funding and public concerns over dam removal, long term longitudinal studies that cover multiple trophic levels are difficult to find. Fortunately, the University of Michigan Biological Station has been involved in the ecological monitoring of a headwater river (the Maple River) in the northern part of the lower peninsula of Michigan. The physical, chemical, and some biological aspects of this river's ecology was measured for eight years prior to dam removal, during dam removal, and for two years post-dam removal. The results presented here show that the ecology of the river recovered within this two-year period, but had a different ecological set point. This new habitat is primarily driven by increases in flow, ammonia, silica, and increases in the populations of two macroinvertebrate feeding guilds. Discharge increased seven-fold in the year that the dam was removed in two sampling sites furthest from the dam but returned to pre-dam removal conditions a year after removal occurred. Turbidity followed this same temporal pattern as turbidity increased during dam removal but decreased to pre-removal levels once the dam was removed. pH decreased at all sites post-removal. In addition, ammonia showed a five-fold increase following dam removal at the two most upstream sites, while phosphate increased at all sites. Last, the number of filterers and shredders increased at all sampling sites, though the significance of increase varied spatially for each guild. The results and observations presented here may provide some guidance for other long term monitoring studies.

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

Evidence-based clinical practice guideline for the pharmacologic management of acute dental pain in children: A report from the American Dental Association Science and Research Institute, the University of Pittsburgh School of Dental Medicine, and the Center for Integrative Global Oral Health at the University of Pennsylvania.

BACKGROUND: A guideline panel convened by the American Dental Association Council on Scientific Affairs, American Dental Association Science and Research Institute, University of Pittsburgh School of Dental Medicine, and Center for Integrative Global Oral Health at the University of Pennsylvania conducted a systematic review and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after 1 or more simple and surgical tooth extractions and the temporary management of toothache (that is, when definitive dental treatment not immediately available) associated with pulp and furcation or periapical diseases in children (< 12 years). TYPES OF STUDIES REVIEWED: The authors conducted a systematic review to determine the effect of analgesics and corticosteroids in managing acute dental pain. They used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations. RESULTS: The panel formulated 7 recommendations and 5 good practice statements across conditions. There is a small beneficial net balance favoring the use of nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen compared with not providing analgesic therapy. There is no available evidence regarding the effect of corticosteroids on acute pain after surgical tooth extractions in children. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications, specifically nonsteroidal anti-inflammatory drugs like ibuprofen and naproxen alone or in combination with acetaminophen, are recommended for managing acute dental pain after 1 or more tooth extractions (that is, simple and surgical) and the temporary management of toothache in children (conditional recommendation, very low certainty). According to the US Food and Drug Administration, the use of codeine and tramadol in children for managing acute pain is contraindicated.

Corticosteroids for managing acute pain subsequent to surgical extraction of mandibular third molars: A systematic review and meta-analysis.

BACKGROUND: Corticosteroids are used to manage pain after surgical tooth extractions. The authors assessed the effect of corticosteroids on acute postoperative pain in patients undergoing surgical tooth extractions of mandibular third molars. TYPES OF STUDIES REVIEWED: The authors conducted a systematic review and meta-analysis. The authors searched the Epistemonikos database, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the US clinical trials registry (ClinicalTrials.gov) from inception until April 2023. Pairs of reviewers independently screened titles and abstracts, then full texts of trials were identified as potentially eligible. After duplicate data abstraction, the authors conducted random-effects meta-analyses. Risk of bias was assessed using Version 2 of the Cochrane Risk of Bias tool and certainty of the evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Forty randomized controlled trials proved eligible. The evidence suggested that corticosteroids compared with a placebo provided a trivial reduction in pain intensity measured 6 hours (mean difference, 8.79 points lower; 95% CI, 14.8 to 2.77 points lower; low certainty) and 24 hours after surgical tooth extraction (mean difference, 8.89 points lower; 95% CI, 10.71 to 7.06 points lower; very low certainty). The authors found no important difference between corticosteroids and a placebo with regard to incidence of postoperative infection (risk difference, 0%; 95% CI, -1% to 1%; low certainty) and alveolar osteitis (risk difference, 0%; 95% CI, -3% to 4%; very low certainty). PRACTICAL IMPLICATIONS: Low and very low certainty evidence suggests that there is a trivial difference regarding postoperative pain intensity and adverse effects of corticosteroids administered orally, submucosally, or intramuscularly compared with a placebo in patients undergoing third-molar extractions.

Analgesics for the management of acute dental pain in the pediatric population: A systematic review and meta-analysis.

BACKGROUND: The authors assessed the clinical effectiveness of analgesics to manage acute pain after dental extractions and pain associated with irreversible pulpitis in children. TYPES OF STUDIES REVIEWED: The authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and US Clinical Trials registry from inception through November 2020. They included randomized controlled trials comparing any pharmacologic interventions with each other and a placebo in pediatric participants undergoing dental extractions or experiencing irreversible pulpitis. After duplicate screening and data abstraction, the authors conducted random-effects meta-analyses. They assessed risk of bias using the Cochrane Risk of Bias 2.0 tool and certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The authors included 6 randomized controlled trials reporting 8 comparisons. Ibuprofen may reduce pain intensity compared with acetaminophen (mean difference [MD], 0.27 points; 95% CI, -0.13 to 0.68; low certainty) and a placebo (MD, -0.19 points; 95% CI, -0.58 to 0.21; low certainty). Acetaminophen may reduce pain intensity compared with a placebo (MD, -0.13 points; 95% CI, -0.52 to 0.26; low certainty). Acetaminophen and ibuprofen combined probably reduce pain intensity compared with acetaminophen alone (MD, -0.75 points; 95% CI, -1.22 to -0.27; moderate certainty) and ibuprofen alone (MD, -0.01 points; 95% CI, -0.53 to 0.51; moderate certainty). There was very low certainty evidence regarding adverse effects. PRACTICAL IMPLICATIONS: Several pharmacologic interventions alone or in combination may provide a beneficial effect when managing acute dental pain in children. There is a paucity of evidence regarding the use of analgesics to manage irreversible pulpitis.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial.

B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA0 with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA0 rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.

Injectable and topical local anesthetics for acute dental pain: 2 systematic reviews.

BACKGROUND: Local anesthesia is essential for pain control in dentistry. The authors assessed the comparative effect of local anesthetics on acute dental pain after tooth extraction and in patients with symptomatic irreversible pulpitis. TYPES OF STUDIES REVIEWED: The authors searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and the US Clinical Trials registry through November 21, 2020. The authors included randomized controlled trials (RCTs) comparing long- vs short-acting injectable anesthetics to reduce pain after tooth extraction (systematic review 1) and evaluated the effect of topical anesthetics in patients with symptomatic pulpitis (systematic review 2). Pairs of reviewers screened articles, abstracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. The authors assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Fourteen RCTs comparing long- vs short-acting local anesthetics suggest that bupivacaine may decrease the use of rescue analgesia and may not result in additional adverse effects (low certainty evidence). Bupivacaine probably reduces the amount of analgesic consumption compared with lidocaine with epinephrine (mean difference, -1.91 doses; 95% CI, -3.35 to -0.46; moderate certainty) and mepivacaine (mean difference, -1.58 doses; 95% CI, -2.21 to -0.95; moderate certainty). Five RCTs suggest that both benzocaine 10% and 20% may increase the number of people experiencing pain reduction compared with placebo when managing acute irreversible pulpitis (low certainty). PRACTICAL IMPLICATIONS: Bupivacaine may be superior to lidocaine with epinephrine and mepivacaine with regard to time to and amount of analgesic consumption. Benzocaine may be superior to placebo in reducing pain for 20 through 30 minutes after application.

Like a rolling stone: Psychotherapy without (episodic) memory.

People with profound amnesia still retain the capacity to learn about the emotional value of experiences, which is crucial in developing and sustaining interpersonal relationships. In a 2017 paper, we demonstrated for the first time (with patient JL) that transferential feelings develop across the therapeutic process, despite profound episodic memory impairment after medial temporal lesions. This paper reports a second case (GA) of a profoundly amnesic patient in psychotherapy, this time after lesions to the anterior fornix. The work with GA opens issues such as the differences and similarities to the previous case, counter-transference phenomena, and the effects of hyperphagia. The findings make it clear that many phenomena are common to both GA and JL, such as forgetfulness, various types of repetition, the importance of the therapeutic alliance, and the ability to make therapeutic gain. However, there were differences between the cases, for example as regards confabulation, which may relate to either pre-morbid personality or lesion site. The paper also discusses the way in which patients of this type bear the very status of psychotherapeutic work with profoundly amnesic patients. Where others have seen barriers and in principle problems in working with such patients, we see many opportunities.

Differing behavioral changes in crayfish and bluegill under short- and long-chain PFAS exposures: Field study in Northern Michigan, USA.

The emergent contaminant family, per- and poly-fluorinated alkyl substances (PFAS) has gained research attention due to their widespread detection and stability within the environment. Despite the growing amount of research on perfluorooctanesulfonic acid (PFOS) and perfluoro-n-octanoic acid (PFOA) in aquatic organisms, investigations detailing behavioral and physiological effects of aquatic organisms exposed to a mixture of PFAS analytes in the wild have been limited. The objective of this study was to evaluate the potential behavioral and histological effects of environmental exposure to PFAS compounds within multiple trophic levels of aquatic ecosystems. The current study investigates effects of environmentally relevant PFAS concentration exposures in crayfish (Faxonius immunis, F. rusticus, F. virilis) and bluegill (Lepomis macrochirus) sourced from four water bodies in Northern Michigan. Antipredator response and foraging behavioral assays were used to investigate potential effects on crayfish; a swimming speed behavioral assay and liver and gill histology analysis were used to investigate potential effects on fish. Linear mixed model and multiple regression analyses resulted in significant relationships between tissue accumulation levels of long chain PFAS compounds and crayfish foraging and fish critical swimming speed responses. Crayfish foraging decreased and fish critical swim speeds increased with PFAS exposure which may lead to energetic and population concerns. Antipredator response in crayfish and liver and gill histology in fish were not significantly related to PFAS tissue or water concentrations. The sensitivity of crayfish and bluegill behavior contributes to the growing body of research regarding the differential toxicity of short-chain and long-chain PFAS compounds. The sensitivity of some aquatic organism behaviors to PFAS accumulated in tissue may have implications for PFAS transfer and alterations to ecosystem functioning; based on the results of this field study, further laboratory research is recommended to further evaluate these relationships.

Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody-drug Conjugate Targeting ADAM9-expressing Tumors.

ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non-small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody-drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial.

BACKGROUND: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)-targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. METHODS: In this phase I/II study, patients received intravenous enoblituzumab (3-15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non-small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]-naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. RESULTS: Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. CONCLUSIONS: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. TRIAL REGISTRATION NUMBER: NCT02475213.

Initial opioid prescribing and subsequent opioid use after dental procedures among opioid-naive patients in Pennsylvania Medicaid, 2012 through 2017.

BACKGROUND: Little is known about how opioid prescribing differs for dental procedures with low, moderate, or high pain or whether that prescribing is associated with continued opioid use. METHODS: The authors used Pennsylvania Medicaid claims data from 2012 through 2017. They categorized dental procedures into 3 groups of pain (low, moderate, high). Using multivariable logistic regression models with random intercept, the authors estimated the probability of receiving an initial opioid prescription within 7 days before and 3 days after a dental procedure associated with the pain categories and assessed subsequent short- and long-term (4-90 days and 91-365 days, respectively) opioid use. RESULTS: The authors identified 1,345,360 index dental procedures (among 912,121 enrollees), of which 67.6% were categorized as low pain, 1.6% as moderate pain, and 30.9% as high pain. Predicted probability of an initial opioid prescription was 2.4% (95% CI, 2.4% to 2.5%) for low-pain, 8.3% (95% CI, 7.9% to 8.6%) for moderate-pain, and 31.8% (95% CI, 31.6% to 31.9%) for high-pain procedures. Predicted probabilities for short-term use for those who did not fill versus those who did fill an opioid prescription were 0.9% (95% CI, 0.9% to 1.0%) versus 25.0% (95% CI, 24.5% to 25.6%) for the low-pain, 1.6% (95% CI, 1.4% to 1.8%) versus 16.6% (95% CI, 14.9% to 18.4%) for moderate-pain, and 2.9% (95% CI, 2.8% to 3.0%) versus 13.5% (95% CI, 13.3% to 13.7%) for the high-pain groups. CONCLUSIONS: Although enrollees undergoing high-pain dental procedures were more likely to fill an initial opioid prescription than their counterparts with low- to moderate-pain procedures, the relative risk of experiencing sustained opioid use (4-90 days postprocedure) was highest in the low-pain group. PRACTICAL IMPLICATIONS: More attention should be paid to reducing opioid prescribing for dental procedures with low pain risk.

Running away or running to? Do prey make decisions solely based on the landscape of fear or do they also include stimuli from a landscape of safety?

Predator-prey interactions are a key part of ecosystem function, and non-consumptive effects fall under the landscape of fear theory. Under the landscape of fear, the antipredator responses of prey are based on the spatial and temporal distribution of predatory cues in the environment. However, the aversive stimuli (fear) are not the only stimuli prey can utilize when making behavioral decisions. Prey might also be using attractive stimuli that represent safety to guide decision making. Using a novel, orthogonal design, we were able to spatially separate aversive and attractive stimuli to determine whether prey are utilizing safety cues to navigate their environment. Crayfish Faxonius rusticus were placed in the center of a behavioral arena. Aversive stimuli of either predatory bass Micropterus salmoides cues or conspecific alarm cues increased along the x-axis of the behavioral arena. Safety cues (shelters) increased along the y-axis by decreasing the number of shelter openings in this direction. Crayfish were allowed two phases to explore the arena: one without the fearful stimuli and one with the stimuli. Linear mixed models were conducted to determine whether movement behaviors and habitat utilization were affected by the phase of the trial and the type of aversive stimuli. Crayfish responded more strongly to alarm cues than to fear cues, with only alarm cues significantly impacting habitat utilization. When responding to alarm cues, crayfish used safety cues as well as fear cues to relocate themselves within the arena. Based on these results, we argue that crayfish utilize a landscape of safety in conjunction with a landscape of fear when navigating their environment.

Spatial, but not temporal, aspects of orientation are controlled by the fine-scale distribution of chemical cues in turbulent odor plumes.

Orientation within turbulent odor plumes occurs across a vast range of spatial and temporal scales. From salmon homing across featureless oceans to microbes forming reproductive spores, the extraction of spatial and temporal information from chemical cues is a common sensory phenomenon. Yet, given the difficulty of quantifying chemical cues at the spatial and temporal scales used by organisms, discovering what aspects of chemical cues control orientation behavior has remained elusive. In this study, we placed electrochemical sensors on the carapace of orienting crayfish and measured, with fast temporal rates and small spatial scales, the concentration fluctuations arriving at the olfactory appendages during orientation. Our results show that the spatial aspects of orientation (turning and heading angles) are controlled by the temporal aspects of odor cues.

A humanized CD3ε-knock-in mouse model for pre-clinical testing of anti-human CD3 therapy.

Pre-clinical murine models are critical for translating drug candidates from the bench to the bedside. There is interest in better understanding how anti-human CD3 therapy works based on recent longitudinal studies of short-term administration. Although several models have been created in this pursuit, each have their own advantages and disadvantages in Type-1 diabetes. In this study, we report a murine genetic knock-in model which expresses both a murine and a humanized-CD3ε-exon, rendering it sensitive to manipulation with anti-human CD3. These huCD3εHET mice are viable and display no gross abnormalities. Specifically, thymocyte development and T cell peripheral homeostasis is unaffected. We tested immune functionality of these mice by immunizing them with T cell-dependent antigens and no differences in antibody titers compared to wild type mice were recorded. Finally, we performed a graft-vs-host disease model that is driven by effector T cell responses and observed a wasting disease upon transfer of huCD3εHET T cells. Our results show a viable humanized CD3 murine model that develops normally, is functionally engaged by anti-human CD3 and can instruct on pre-clinical tests of anti-human CD3 antibodies.

Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule.

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67+CD8 and ICOS+CD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.