The weather determines the number of cases of tick paralysis in dogs and cats in eastern Australia, caused by Ixodes holocyclus, the eastern paralysis tick.

We studied over 222,000 cases of emergency veterinary consultations in four regions along the eastern coast of Australia. We found that cases of tick paralysis (TP) caused by the eastern paralysis tick, Ixodes holocyclus, accounted for 7.5% of these cases: >16,000 cases. The season of TP and the number (prevalence) of TP cases varied among regions and over the years. Our study of the association between weather and (i) the start of the season of TP, and (ii) the number of TP cases revealed much about the intricate relationship between the weather and I. holocyclus. We studied the effect of the hypothetical availability of isoxazoline-containing tick-preventative medicines and found that an increase in the availability of these medicines had significantly contributed to the decrease in TP cases. We found that the weather in winter accounted for the time of the year the season of TP starts whereas the weather in summer accounted for the number of TP cases in the TP season. Last, through a study of the effects of shifts in the climate under four hypothetical scenarios (warmer/cooler and drier/wetter than average), we propose that the start of the season of TP depends on how soon the weather in winter becomes suitable for the activity (e.g. host-seeking) and the development of I. holocyclus nymphs, and that the number of TP cases during the TP season depends on how many engorged female ticks and their eggs survive during summer.

Tree-ring δ15N as an indicator of nitrogen dynamics in stands with N2-fixing Alnus rubra.

Tree-ring δ15N may depict site-specific, long-term patterns in nitrogen (N) dynamics under N2-fixing species, but field trials with N2-fixing tree species are lacking and the relationship of temporal patterns in tree-ring δ15N to soil N dynamics is controversial. We examined whether the tree-ring δ15N of N2-fixing red alder (Alnus rubra Bong.) would mirror N accretion rates and δ15N of soils and whether the influence of alder-fixed N could be observed in the wood of a neighboring conifer. We sampled a 27-year-old replacement series trial on south-eastern Vancouver Island, with red alder and coastal Douglas-fir (Pseudotsuga menziesii [Mirb.] Franco) planted in five proportions (0/100, 11/89, 25/75, 50/50 and 100/0) at a uniform stem density. An escalation in forest floor N content was evident with an increasing proportion of red alder, equivalent to a difference of ~750 kg N ha-1 between 100% Douglas-fir versus 100% alder. The forest floor horizon also had high δ15N values in treatments with more red alder. Red alder had a consistent quadratic fit in tree-ring δ15N over time, with a net increase of $\sim$1.5‰, on average, from initial values, followed by a plateau or slight decline. Douglas-fir tree-ring δ15N, in contrast, was largely unchanged over time (in three of four plots) but was significantly higher in the 50/50 mix. The minor differences in current leaf litter N content and δ15N between alder and Douglas-fir, coupled with declining growth in red alder, suggests the plateau or declining trend in alder tree-ring δ15N could coincide with lower N2-fixation rates, potentially by loss in alder vigor at canopy closure, or down-regulation via nitrate availability.

Impact of war on veteran life span: natural experiment involving combat versus non-combat exposed military personnel.

INTRODUCTION: There is still uncertainty around the impact of combat exposure on the life span of war veterans. Therefore we made use of a natural experiment to study the impact on veteran life span of combat versus non-combat exposure in World War II (WW2). METHODS: The combat-exposed military personnel were derived from a random (10%) sample of the military roll of the 28th (Maori) Battalion from New Zealand. One non-combat cohort was the 15th Reinforcements of this same Battalion, since the war ended before they reached the front line. The other non-combat cohort were Maori personnel who were only involved in Jayforce, which occupied Japan at the end of the WW2. Data on life span were mainly derived from an official repository of birth and death records, but supplemented with other sources, including military files. RESULTS: When comparing life spans of service veterans, there was no statistically significant reduction for the average life span of the 234 combat-exposed veterans in our sample from the 28th (Maori) Battalion (66.7 years), relative to the Maori veterans from two non-combat cohorts: the 132 personnel in the 15th Reinforcements (67.2 years) and the 147 personnel in Jayforce (66.9 years). CONCLUSIONS: Despite a very high level of wounding in the combat-exposed group (48%), there were no statistically significant reductions in life span between this group and comparable non-combat exposed veterans. This finding contrasts to life span reductions found in a similar study of New Zealand veterans of WW1.

Differential lifespan impacts on veterans by war exposure in the First World War.

INTRODUCTION: There remains uncertainty around the impact of war on the lifespan of First World War (WW1) veterans. In particular, study comparison groups do not typically consider the 'healthy soldier effect'. METHODS: We obtained lifespan data on a random sample of 857 war-exposed New Zealand WW1 veterans and compared this with lifespans of a non-war military cohort (n=1039). This comparison was possible as the non-war-cohort arrived in Europe too late to participate in the war, allowing a 'natural experiment' that avoided the 'healthy solider effect'. RESULTS: The lifespan comparisons indicated lower mean lifespan in the war-exposed veteran cohort compared with the non-war veteran cohort (69.7 vs 71.1 years; p=0.0405). This gap persisted (range: 0.8-1.1 years) but was no longer statistically significant when only considering the non-Maori ethnic grouping (nearly all European/Pakeha personnel), when excluding additional deaths in the immediate postwar period up to 31 December 1923, and when excluding participation in any other wars. This was the case in both analysis of variance and Cox proportional hazards regression adjusting for year of birth and occupational status. Within the war-exposed cohort, there were suggestive patterns of increasing lifespan with increasing occupational status and military rank (eg, 69.5, 70.0 and 70.7 mean years as group-level occupational status progressively increased). There were also stark differences in lifespan of 8.3 years between Maori (Indigenous) and non-Maori veterans (p=0.0083). CONCLUSIONS: The pattern of reduced lifespan in war-exposed versus non-war-exposed veterans was compatible with a smaller previous New Zealand study with comparable methodology. Veterans who were Maori had significantly lower lifespans than non-Maori veterans. There are a number of feasible avenues to further improve this type of work with existing data sources.

Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer.

PURPOSE: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. EXPERIMENTAL DESIGN: Biopsies from patients with ROS1 + NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. RESULTS: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%). CONCLUSIONS: ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.

Leadership, Inside and Out: The Tideswell-AGS-ADGAP Emerging Leaders in Aging Program.

BACKGROUND/OBJECTIVES: To optimize health and well-being for all older people, we must collectively develop leaders to pioneer models of care, educate the healthcare workforce, advance research, and engage the community. METHODS: The Emerging Leaders in Aging (ELIA) program was created to train a multiprofessional cadre of leaders focused on the health and well-being of older people. ELIA uses the social change curricular framework and addresses knowledge of self, community, and engagement with change. Program impact measured included scholar satisfaction, confidence related to curricular domains before and after the program, project progress, and scholar productivity. RESULTS: Four cohorts of 65 scholars in seven health professions from 24 states were selected for the year-long 55-hour program. Overall satisfaction from members of the first three cohorts who have completed the program (n = 46) was 4.86 (scale = 1-5), and scholar confidence increased from 5.8 to 8.0 (scale = 1-9) (p < .001). These scholars reported 85 presentations, 63 publications, and 21 awards subsequent to training. All scholars described the importance of a program focused on early and mid-career leaders in health and aging. DISCUSSION: The ELIA program leverages longitudinal, distance mentor communities, and project-based learning strategies. It has improved confidence and skills in emerging leaders who commit their efforts toward the care of older persons. Programs like ELIA are critical to preparing a healthcare workforce to optimize care for all as our health needs and expectations change with age. J Am Geriatr Soc 67:437-442, 2019.

Psychosocial needs of young breast cancer survivors in Mexico City, Mexico.

OBJECTIVE: Young breast cancer survivors in Mexico face distinct psychosocial challenges that have not been characterized. This study aims to describe the psychosocial needs of young breast cancer survivors in Mexico at 5 or more years of survivorship, identifying areas of focus for early interventions. METHODS: Breast cancer patients diagnosed at age 40 or prior with 5 or more years since diagnosis were invited to participate in one-on-one 30-60 minute semi-structured audio-recorded interviews at the Instituto Nacional de Cancerología in Mexico City. Transcripts were coded using thematic analysis with NVivo software. RESULTS: 25 women participated. Five major phenomena emerged from analysis: (1) minimization of fertility concerns; (2) persistence of body image disturbance over time; (3) barriers to employment during survivorship; (4) impact on family relationships and social networks; & (5) unmet psychological care and informational needs. CONCLUSIONS: Early interventions with a focus on fertility loss education, access to reconstructive surgery and body image support, guidance during return-to-work, assistance with childcare, integration of psychological care and the fulfillment of informational needs could ameliorate long-term psychological and social distress for young breast cancer survivors in Mexico.

Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer.

INTRODUCTION: Intracranial metastases are a common cause of morbidity and mortality in patients with advanced NSCLC, and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. METHODS: We identified patients with advanced NSCLC with brain metastases who received cranial RT and were treated with or without programmed cell death 1/programmed death ligand 1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. RESULTS: Of 163 patients, 50 (31%) received ICIs, whereas 113 (69%) were ICI naive. Overall, 94 (58%), 28 (17%), and 101 (62%) patients received stereotactic radiosurgery, partial brain irradiation, and/or whole brain RT, respectively. Fifty percent of patients received more than one radiation course. We observed no significant difference in rates of all-grade AEs and grade 3 or higher AEs between the ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs in 8% of ICI-naive patients versus in 9% of ICI-treated patients for stereotactic radiosurgery [p = 1.00] and in 8% of ICI-naive patients versus in 10% of ICI-treated patients for whole brain RT [p = 0.71]). Additionally, there was no difference in AE rates on the basis of timing of ICI administration with respect to RT. CONCLUSIONS: Treatment with an ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of programmed cell death 1/programmed death ligand 1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.

Is it time for comprehensive geriatric assessment to move beyond primary care? The case for targeting medical sub-specialty practice.

Comprehensive geriatric assessment (CGA) as a consultative service for older adults with complex medical and psychosocial challenges has existed for decades. However, studies have often showed inconsistent acceptance and implementation of geriatric recommendations by primary care providers (PCPs) raising doubts about the overall benefits of CGA in this setting. Press and colleagues investigated the patient- and provider-related factors that affect recommendation implementation, and like previous studies, they too found similarly low rates of implementation. In this commentary, we acknowledge the perennial challenges that exist to improving the acceptance of CGA in primary care practice, and we suggest an alternative target: medical sub-specialty practice. By highlighting three medical sub-specialty fields (oncology, nephrology, and cardiology), which have demonstrated that CGA can be incorporated into their respective clinical practices, we argue that CGA may prove to have greater impact in these settings than in primary care. We also propose initial research steps that could further delineate the trends, outcomes, and next steps for such consultations.

Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer.

PURPOSE: The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among ROS1-positive patients are limited. PATIENTS AND METHODS: We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of ROS1-positive patients progressing on crizotinib. RESULTS: We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. ROS1-positive patients had significantly lower rates of extrathoracic metastases (ROS1 59.0%, ALK 83.2%, P=0.002), including lower rates of brain metastases (ROS1 19.4%, ALK 39.1%; P = 0.033), at initial metastatic diagnosis. Despite similar overall survival between ALK- and ROS1-positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; P=0.786), ROS1-positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; P<0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. ROS1 mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). CONCLUSIONS: Compared to ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.

Bridging barriers to clinic-based HIV testing with new technology: translating self-implemented testing for African American youth.

Numerous barriers to clinic-based HIV testing exist (e.g., stigmatization) for African American youth. These barriers may be addressed by new technology, specifically HIV self-implemented testing (SIT). We conducted a series of formative phase 3 translation studies (49 face-to-face interviews, 9 focus groups, 1 advisory panel review) among low-income African American youth (15-19 years) and providers of adolescent services in two US cities to identify potential translation difficulties of the OraQuick SIT. Based on content analysis, we found that providers and African American youth viewed SITs positively compared to clinic-based testing. Data suggest that SITs may reduce social stigma and privacy concerns and increase convenience and normalization of HIV testing. Challenges with SIT implementation include difficulties accessing confirmatory testing, coping with adverse outcomes, and instructional materials that may be inappropriate for low socioeconomic status (SES) persons. Study results underscore the need for translation studies to identify specific comprehension and implementation problems African American youth may have with oral SITs.