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IntroductionThis is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease.Methods16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics.ResultsWe identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine.DiscussionThese data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

Purpose: Brain metastases are common among adult patients with solid malignancies and are increasingly being treated with stereotactic radiosurgery (SRS). As more patients with brain metastases are becoming eligible for SRS, there is a need for practical review of patient selection and treatment considerations. Methods and Materials: Two patient cases were identified to use as the foundation for a discussion of a wide and representative range of management principles: (A) SRS alone for 5 to 15 lesions and (B) a large single metastasis to be treated with pre- or postoperative SRS. Patient selection, fractionation, prescription dose, treatment technique, and dose constraints are discussed. Literature relevant to these cases is summarized to provide a framework for treatment of similar patients. Results: Treatment of brain metastases with SRS requires many considerations including optimal patient selection, fractionation selection, and plan optimization. Conclusions: Case-based practice guidelines developed by the Radiosurgery Society provide a practical guide to the common scenarios noted above affecting patients with metastatic brain tumors.

Summary: Background: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. Methods: 76 healthy adults aged 18–64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 μg, N = 32), mRNA vaccine (10, 20, or 50 μg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. ClinicalTrials.gov NCT05272605. Findings: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. Interpretation: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. Funding: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

Summary: Background: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. Methods: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. Findings: Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The ‘beta variant’ RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. Interpretation: These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. Funding: This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.

Real-time multi-axis distributed tactile sensing is a critical capability if robots are to perform stable gripping and dexterous manipulation, as it provides crucial information about the sensor–object interface. In this paper, we present an optical-based six-axis tactile sensor designed in a fingertip shape for robotic dexterous manipulation. The distributed sensor can precisely estimate the local XYZ force and displacement at ten distinct locations and provide the global XYZ force and torque measurements. Its compact size, comparable to that of a human thumb, and minimal thickness allow seamless integration onto existing robotic fingers, eliminating the need for complex modifications to the gripper. The proposed sensor design uses a simple, low-cost fabrication method. Moreover, the optical transduction approach uses light angle and intensity sensing to infer force and displacement from deformations of the individual sensing units that form the overall sensor, providing distributed six-axis sensing. The local force precision at each sensing unit in the X, Y, and Z axes is 20.89 mN, 19.19 mN, and 43.22 mN, respectively, over a local force range of approximately ±1.5 N in X and Y and 0 to −2 N in Z. The local displacement precision in the X, Y, and Z axes is 56.70 μm, 50.18 μm, and 13.83 μm, respectively, over a local displacement range of ±2 mm in the XY directions and 0 to −1.5 mm in Z (i.e., compression). Additionally, the sensor can measure global torques, Tx, Ty, and Tz, with a precision of of 1.90 N-mm, 1.54 N-mm, and 1.26 N-mm, respectively. The fabricated design is showcased by integrating it with an OnRobot RG2 gripper and illustrating real-time measurements during in simple demonstration task, which generated changing global forces and torques.

Abstract Background We hypothesized that the total volume of metastases at initial oligometastatic (OM) presentation to stereotactic body radiation therapy (SBRT) is an important prognostic factor that can refine the definition of OM disease. Methods Patients with extracranial oligometastatic cancer (≤5 lesions) treated with SBRT were included in an international multi‐institutional database. Multivariable Cox and competing risks regression models were used to determine the relationship between distant progression‐free survival (DPFS), widespread progression (WSP), and overall survival (OS) with the total planning target volume (PTV) at initial OM presentation to SBRT. All models were adjusted for histology, pre‐SBRT systemic therapy, osseous‐only lesions, and number of metastases. Results In total, 961 patients were included. The median follow‐up was 24.4 months (IQR: 13.8–37.5). Total PTV had a significant effect on DPFS in the first 18 months after SBRT and was most profound in the first 6 months, when each twofold increase in total PTV conferred a 40.6% increased risk of distant progression (p

Summary: The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.

Abstract Background Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastatic disease (OMD), but the effect of metastasis timing on patient outcomes remains uncertain. Methods An international database of patients with OMD treated with SBRT was assembled with rigorous quality assurance. Early versus late metastases were defined as those diagnosed ≤24 versus >24 months from the primary tumor. Overall survival (OS), progression‐free survival (PFS), and incidences of wide‐spread progression (WSP) were estimated using multivariable Cox proportional hazard models stratified by primary tumor types. Results The database consists of 1033 patients with median follow‐up of 24.1 months (0.3–104.7). Late metastatic presentation (N = 427) was associated with improved OS compared to early metastasis (median survival 53.6 vs. 33.0 months, hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.47–0.72, p

Abstract Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.

Background: In spinal oncology, titanium implants pose several challenges including artifact on advanced imaging and therapeutic radiation perturbation. To mitigate these effects, there has been increased interest in radiolucent carbon fiber (CF) and CF-reinforced polyetheretherketone (CFR-PEEK) implants as an alternative for spinal reconstruction. This study surveyed the members of the North American Spine Society (NASS) section of Spinal Oncology to query their perspectives regarding the clinical utility, current practice patterns, and recommended future directions of radiolucent spinal implants. Methods: In February 2021, an anonymous survey was administered to the physicians of the NASS section of Spinal Oncology. Participation in the survey was optional. The survey contained 38 items including demographic questions as well as multiple-choice, yes/no questions, Likert rating scales, and short free-text responses pertaining to the “clinical concept”, “efficacy”, “problems/complications”, “practice pattern”, and “future directions” of radiolucent spinal implants. Results: Fifteen responses were received (71.4% response rate). Six of the participants (40%) were neurosurgeons, eight (53.3%) were orthopedic surgeons, and one was a spinal radiation oncologist. Overall, there were mixed opinions among the specialists. While several believed that radiolucent spinal implants provide substantial benefits for the detection of disease recurrence and radiation therapy options, others remained less convinced. Ongoing concerns included high costs, low availability, limited cervical and percutaneous options, and suboptimal screw and rod designs. As such, participants estimated that they currently utilize these implants for 27.3% of anterior and 14.7% of all posterior reconstructions after tumor resection. Conclusion: A survey of the NASS section of Spinal Oncology found a lack of consensus with regards to the imaging and radiation benefits, and several ongoing concerns about currently available options. Therefore, routine utilization of these implants for anterior and posterior spinal reconstructions remains low. Future investigations are warranted to practically validate these devices’ theoretical risks and benefits.

Purpose: To inform development of procedures for using tumor-treating field arrays (TTFields) during glioblastoma radiation therapy by determining whether the placement and repositioning of arrays affects target volume coverage and cranial skin dose. Methods and Materials: Radiation plans from 10 consecutive patients treated for glioblastoma were copied to a cranial phantom and reoptimized for phantom anatomy. Dose distributions were then recalculated on 3 additional computed tomographic scans of the phantom with the TTFields electrode arrays placed over distinct locations on the phantom scalp to compare planning target volume (PTV) coverage and skin dose with and without TTFields in place in varying positions. Percent depth dose curves were also measured for radiation beams passing through the electrodes and compared with commonly used bolus material. Results: The presence of TTFields arrays decreased PTV V97% and D97% by as much as 1.7% and 2.7%, respectively, for a single array position, but this decrease was mitigated by array repositioning. On averaging the 3 array positions, there was no statistically significant difference in any dosimetric parameter of PTV coverage (V95-97%, D95-97%) across all cases compared with no array. Mean increases in skin D1cc and D20cc of 3.1% were calculated for the cohort. Surface dose for TTFields electrodes was less than that with a 5-mm superflab bolus. Conclusions: Our work demonstrates that placement of TTFields arrays does not significantly affect target volume coverage. We show that repositioning of TTFields arrays, as is required in clinical use, further minimizes any dosimetric changes and eliminates the need for replanning when arrays are moved. A slight, expected bolus effect is observed, but the calculated increases in skin dose are not clinically significant. These data support the development of clinical trials to assess the safety and efficacy of combining concurrent chemoradiotherapy with TTFields therapy for glioblastoma.

BackgroundPatients hospitalized with acute coronary syndrome (ACS) or heart failure (HF) are frequently readmitted. This is the first randomized controlled trial of a mobile health intervention that combines telemonitoring and education for inpatients with ACS or HF to prevent readmission. ObjectiveThis study aims to investigate the feasibility, efficacy, and cost-effectiveness of a smartphone app–based model of care (TeleClinical Care [TCC]) in patients discharged after ACS or HF admission. MethodsIn this pilot, 2-center randomized controlled trial, TCC was applied at discharge along with usual care to intervention arm participants. Control arm participants received usual care alone. Inclusion criteria were current admission with ACS or HF, ownership of a compatible smartphone, age ≥18 years, and provision of informed consent. The primary end point was the incidence of unplanned 30-day readmissions. Secondary end points included all-cause readmissions, cardiac readmissions, cardiac rehabilitation completion, medication adherence, cost-effectiveness, and user satisfaction. Intervention arm participants received the app and Bluetooth-enabled devices for measuring weight, blood pressure, and physical activity daily plus usual care. The devices automatically transmitted recordings to the patients’ smartphones and a central server. Thresholds for blood pressure, heart rate, and weight were determined by the treating cardiologists. Readings outside these thresholds were flagged to a monitoring team, who discussed salient abnormalities with the patients’ usual care providers (cardiologists, general practitioners, or HF outreach nurses), who were responsible for further management. The app also provided educational push notifications. Participants were followed up after 6 months. ResultsOverall, 164 inpatients were randomized (TCC: 81/164, 49.4%; control: 83/164, 50.6%; mean age 61.5, SD 12.3 years; 130/164, 79.3% men; 128/164, 78% admitted with ACS). There were 11 unplanned 30-day readmissions in both groups (P=.97). Over a mean follow-up of 193 days, the intervention was associated with a significant reduction in unplanned hospital readmissions (21 in TCC vs 41 in the control arm; P=.02), including cardiac readmissions (11 in TCC vs 25 in the control arm; P=.03), and higher rates of cardiac rehabilitation completion (20/51, 39% vs 9/49, 18%; P=.03) and medication adherence (57/76, 75% vs 37/74, 50%; P=.002). The average usability rating for the app was 4.5/5. The intervention cost Aus $6028 (US $4342.26) per cardiac readmission saved. When modeled in a mainstream clinical setting, enrollment of 237 patients was projected to have the same expenditure compared with usual care, and enrollment of 500 patients was projected to save approximately Aus $100,000 (approximately US $70,000) annually. ConclusionsTCC was feasible and safe for inpatients with either ACS or HF. The incidence of 30-day readmissions was similar; however, long-term benefits were demonstrated, including fewer readmissions over 6 months, improved medication adherence, and improved cardiac rehabilitation completion. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12618001547235; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375945

BackgroundA novel smartphone app-based model of care (TeleClinical Care – TCC) for patients with acute coronary syndrome (ACS) and heart failure (HF) was evaluated in a two-site, pilot randomised control trial of 164 participants in Sydney, Australia. The program included a telemonitoring system whereby abnormal blood pressure, weight and heart rate readings were monitored by a central clinical team, who subsequently referred clinically significant alerts to the patients' usual general practitioner (GP, also known as primary care physician in the United States), HF nurse or cardiologist. While the primary endpoint, 30-day readmissions, was neutral, intervention arm participants demonstrated improvements in readmission rates over 6 months, cardiac rehabilitation (CR) completion and medication compliance. A process evaluation was designed to identify contextual factors and mechanisms that influenced the results, as well as strategies of improving site and participant recruitment and the delivery of the intervention, for a planned larger effectiveness trial of over 1,000 patients across the state of New South Wales, Australia (TCC-Cardiac).MethodsMultiple data sources were used in this mixed-methods process evaluation, including interviews with four TCC team members, three GPs and three cardiologists. CR completion rates, HF outreach service (HFOS) referrals and cardiologist follow-up appointments were audited. A patient questionnaire was also analysed for evidence of improved self-care as a hypothesised mechanism of the TCC app. An implementation research logic model was used to synthesise our findings.ResultsRates of HFOS referral (83 vs. 72%) and cardiologist follow-up (96 vs. 93%) were similarly high in the intervention and control arms, respectively. Team members were largely positive towards their orientation and training, but highlighted several implementation strategies that could be optimised for TCC-Cardiac: streamlining of the enrolment process, improving the reach of the trial by screening patients in non-cardiac wards, and ensuring team members had adequate time to recruit (>15 h per week). GPs and cardiologists viewed the intervention acceptably regarding potential benefit of closely monitoring, and responding to abnormalities for their patients, though there were concerns of the potential additional workload generated by alerts that did not merit clinical intervention. Clear delineation of which clinician (GP or cardiologist) was primarily responsible for alert management was also recommended, as well as a preference to receive regular summary data. Several patients commented on the mechanisms of improved self-management because of TCC, which could have led to the outcome of improved medication compliance.DiscussionUse of TCC was associated with several benefits, including higher patient engagement and completion rates with CR. The conduct and delivery of TCC-Cardiac will be improved by the findings of this process evaluation to optimise recruitment, and establishing the roles of GPs and cardiologists as part of the model.

Abstract Objectives Following infection with SARS‐CoV‐2, virus‐specific antibodies are generated, which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS‐CoV‐2 has been extensively reported. By comparison, other antibody isotypes including IgA have been poorly characterised. Methods Here, we characterised plasma IgA from 41 early convalescent COVID‐19 subjects for neutralisation and Fc effector functions. Results Convalescent plasma IgA from > 60% of the cohort had the capacity to inhibit the interaction between wild‐type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA‐mediated ACE2 inhibition than matched IgG when tested at equivalent concentrations. Plasma IgA and IgG from this cohort broadly recognised similar RBD epitopes and had similar capacities to inhibit ACE2 from binding to 22 of the 23 prevalent RBD mutations assessed. However, plasma IgA was largely incapable of mediating antibody‐dependent phagocytosis in comparison with plasma IgG. Conclusion Overall, convalescent plasma IgA contributed to the neutralising antibody response of wild‐type SARS‐CoV‐2 RBD and various RBD mutations. However, this response displayed large heterogeneity and was less potent than IgG.

Purpose: Tumor treating fields (TTFields) is a novel antimitotic treatment that was first proven effective for glioblastoma multiforme, now with trials for several extracranial indications underway. Several studies focused on concurrent TTFields therapy with radiation in the same time period, but were not given simultaneously. This study evaluates the targeting accuracy of simultaneous radiation therapy while TTFields arrays are in place and powered on, ensuring that radiation does not interfere with TTFields and TTFields does not interfere with radiation. This is one of several options to enable TTFields to begin several weeks sooner, and opens potential for synergistic effects of combined therapy. Methods: TTFields arrays were attached to a warm saline water bath and salt was added until the TTFields generator reached the maximal 2000 mA peak-to-peak current. A ball cube phantom containing 2 orthogonal films surrounded by fiducials was placed in the water phantom, CT scanned, and a radiation treatment plan with 58 isocentric beams was created using a 3 cm circular collimator. Fiducial tracking was used to deliver radiation, the films were scanned, and end-to-end targeting error was measured with vendor-supplied software. In addition, radiation effects on electric fields generated by the TTFields system were assessed by examining logfiles generated from the field generator. Results: With TTFields arrays in place and powered on, the robotic radiosurgery system achieved a final targeting result of 0.47 mm, which was well within the submillimeter specification. No discernible effects on TTFields current output beyond 0.3% were observed in the logfiles when the radiation beam pulsed on and off. Conclusion: A robotic radiosurgery system was used to verify that radiation targeting was not adversely affected when the TTFields arrays were in place and the TTFields delivery device was powered on. In addition, this study verified that radiation delivered simultaneously with TTFields did not interfere with the generation of the electric fields.

For many bird species, but especially aerial insectivores, reproduction depends on weather. Climate change is likely to intensify effects, but with uncertain consequences. We report 22 years of data on Eastern Kingbird (Tyrannus tyrannus) reproduction for two populations located in different hygric environments undergoing climate change; mesic central New York, USA, (NY; 12 years) and xeric southeastern Oregon, USA, (OR: 10 years). Laying date became earlier with increasing temperature in the 30-day period preceding laying in identical fashion at both sites, and in years of early laying, clutch size was larger, length of laying season increased, and failed initial nesting attempts were more often replaced. High temperature in the 10-days preceding mean laying date was associated with shorter laying seasons, while a site by 10-day temperature interaction reflected an increase and decrease of clutch size with increasing 10-day temperature in NY and OR, respectively. Seasonal rate of clutch size decline was higher when the laying season was short but also slowed in xeric OR when rain was abundant in the 10-days prior to mean laying date. Nest predation drove annual variation in young fledged/nest, but the latter also increased and decreased with increasing maximum temperature during the nestling phase in mesic NY and xeric OR, respectively. Potential effects of climate change on kingbird populations are thus high given the dependence of reproduction on weather, and climate change likely contributed to declines of kingbirds in OR. Declines of kingbirds in NY appear unrelated to warming climates because higher temperatures advanced laying dates and yielded greater nest productivity. However, length of laying season declined across years at both sites, and thus early season gains may be negated by poor conditions late in the season that may be causing shorter laying seasons. Further work is needed to identify causes for the latter changes.