The patient journey to diagnosis and treatment of autoinflammatory diseases.

BACKGROUND: Limited data are available on the experiences of patients with autoinflammatory diseases (AIDs) and their families along the path to diagnosis and treatment. We sought to describe these experiences in patients with AIDs including tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). METHODS: Ninety-minute, semi-structured qualitative interviews and 5-day written/video diaries were used to gather information on the experiences of patients with AIDs and their families. RESULTS: Twelve families of patients from the US (TRAPS [n = 4], MKD/HIDS [n = 5], FMF [n = 5]) participated in this study from August to November 2015. The study included two families with multiple afflicted siblings. Patients' ages ranged from 1 to 28 years. Most parents reported realizing that something was seriously wrong with their child after medical emergencies and/or hospitalizations, which initiated the difficult path to diagnosis. For most, the process included multiple specialist visits, extensive and repeated testing, and many misdiagnoses. Over time, 92% of parents reported losing confidence in the healthcare system's ability to find an answer to their child's symptoms, while they also struggled with unsupportive school personnel and dismissive friends and relatives. Patients and their parents reported holding on to memories of "what life was like" before the onset of symptoms and mourning their subsequent loss of "normalcy." Even after diagnosis, patients and parents continued to feel uncertain about what to expect in the future. CONCLUSIONS: All families emphasized the need for efficient early diagnosis of AIDs. Initiatives that improve the speed and accuracy of diagnosis, provide more comprehensive patient education, and support patients and families through the illness have the potential to significantly improve the quality of life of patients with AIDs and their families. Healthcare providers should be aware of the impact of the long diagnostic journey on families and work to create an environment of trust and collaboration in the face of a difficult and prolonged diagnostic process.

Fine-scale foraging movements by fish-eating killer whales (Orcinus orca) relate to the vertical distributions and escape responses of salmonid prey (Oncorhynchus spp.).

BACKGROUND: We sought to quantitatively describe the fine-scale foraging behavior of northern resident killer whales (Orcinus orca), a population of fish-eating killer whales that feeds almost exclusively on Pacific salmon (Oncorhynchus spp.). To reconstruct the underwater movements of these specialist predators, we deployed 34 biologging Dtags on 32 individuals and collected high-resolution, three-dimensional accelerometry and acoustic data. We used the resulting dive paths to compare killer whale foraging behavior to the distributions of different salmonid prey species. Understanding the foraging movements of these threatened predators is important from a conservation standpoint, since prey availability has been identified as a limiting factor in their population dynamics and recovery. RESULTS: Three-dimensional dive tracks indicated that foraging (N = 701) and non-foraging dives (N = 10,618) were kinematically distinct (Wilks' lambda: λ16 = 0.321, P < 0.001). While foraging, killer whales dove deeper, remained submerged longer, swam faster, increased their dive path tortuosity, and rolled their bodies to a greater extent than during other activities. Maximum foraging dive depths reflected the deeper vertical distribution of Chinook (compared to other salmonids) and the tendency of Pacific salmon to evade predators by diving steeply. Kinematic characteristics of prey pursuit by resident killer whales also revealed several other escape strategies employed by salmon attempting to avoid predation, including increased swimming speeds and evasive maneuvering. CONCLUSIONS: High-resolution dive tracks reconstructed using data collected by multi-sensor accelerometer tags found that movements by resident killer whales relate significantly to the vertical distributions and escape responses of their primary prey, Pacific salmon.

The patient journey in chronic myeloid leukemia patients on tyrosine kinase inhibitor therapies: qualitative insights using a global ethnographic approach.

BACKGROUND: The advent and approval of tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients with chronic myeloid leukemia (CML), which has been transformed into a chronically manageable disease. OBJECTIVE: The objective was to qualitatively assess the effects of diagnosis and treatment on patients with CML to offer recommendations for health-care providers (HCPs) for the better support of patients. METHODS: By use of an ethnographic approach based on in-home interviews, photo journals, and an optional telephone debriefing interview, this study included 50 patients with CML from Brazil, France, Germany, Russia, and Spain, including patients within 18 months of diagnosis and receiving frontline TKI therapy (n = 20), patients between >18 months and 7 years from diagnosis and receiving ongoing frontline therapy (n = 20), and patients who switched to second- or third-line TKI therapy (n = 10). In-home interviews were designed to address patient perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and relationships with HCPs. Transcripts from these interviews and other data were analyzed to identify similar patterns and themes experienced by patients with CML. RESULTS: The investigation generated a five-stage, patient-centered model of the experience of the patient throughout diagnosis, treatment, and management of CML: crisis, hope, adaptation, new normal, and uncertainty. Patients proceeded through these stages in the course of their disease management. The stages were affected by the patients' emotional and social experiences, their knowledge about CML, their positive experiences with their HCPs and/or treatment, and their optimism about their long-term prognosis. CONCLUSIONS: We identified five common stages experienced by patients with CML and suggest several recommendations for HCPs on the management of patients through their disease journey. By providing support, education, and reassurance, HCPs can help patients as they move through the early stages of crisis and hope. When patients are in the adaptation and new-normal stages, HCPs can help patients achieve and maintain a new normality by setting expectations for the risks/benefits of long-term chronic drug therapy and disease monitoring and by continuing to support patient adherence.

Experiences and perspectives on the GIST patient journey.

PURPOSE: The tyrosine kinase inhibitor (TKI) imatinib has improved outcomes for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), and for patients receiving adjuvant therapy following GIST resection. This qualitative study explored the experiences and emotions of patients through GIST diagnosis, treatment initiation, disease control, and in some patients, loss of response and therapy switch. PATIENTS AND METHODS: Ethnographic investigations were conducted, including semi- structured qualitative interviews of patients with resected or metastatic/unresectable GIST and their caregivers, from Canada (n = 15); the United States (n = 10); and Brazil, France, Germany, Russia, and Spain (n = 5 each). Some interviewees also kept 7-day photo journals. Responses were qualitatively analyzed to identify gaps and unmet needs where communication about disease, treatments, and adherence could be effective. RESULTS: Patients shared common experiences during each stage of disease management (crisis, hope, adaptation, new normal, and uncertainty). Patients felt a sense of crisis during diagnosis, followed by hope upon TKI therapy initiation. Over time, they came to adapt to their new lives (new normal) with cancer. With each follow-up, patients confronted the uncertainty of becoming TKI resistant and the possible need to switch therapy. During uncertainty many patients sought new information regarding GIST. Cases of disease progression and drug switching caused patients to revert to crisis and restart their emotional journey. Patients with primary or unresectable/metastatic GIST shared similar journeys, especially regarding uncertainty, although differences in the scope and timing of phases were observed. Strategies patients used to remain adherent included obtaining family support, setting reminder mechanisms, taking medicine at routine times, and storing medicine in prominent places. CONCLUSIONS: Physicians and support staff can manage patient expectations and encourage adherence to therapy, which may facilitate optimal patient outcomes. Patient education about current GIST developments and adherence across all phases of the patient journey are of benefit.

Chemoprevention of prostate cancer with lycopene in the TRAMP model.

BACKGROUND: Dietary lycopene combined with other constituents from whole tomatoes was previously found to have greater chemopreventive effects against prostate cancer as compared to pure lycopene provided in a beadlet formulation. We hypothesized that tomato paste would have greater chemopreventive effects in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice relative to equivalent lycopene doses provided from lycopene beadlets. METHODS: Fifty-nine TRAMP mice were randomized to a control diet or to diets providing 28 mg lycopene per kg diet from tomato paste (TP) or from lycopene beadlet (LB), and sacrificed at 20 weeks. Prostate histopathology, prostate weight and serum levels of IGF-I and IGF binding protein-3 were evaluated. RESULTS: The incidence of prostate cancer was significantly decreased in the LB group relative to the control group (60% vs. 95%, respectively, P = 0.0197) whereas the difference between the TP and control groups was not statistically significant (80% vs. 95%, P = 0.34). There was no difference in prostate weights between the groups. Total lycopene levels in the serum and prostate tissue were similarly elevated in the LB and TP groups relative to the control group. The ratio of 5-cis-lycopene to trans-lycopene in the serum was significantly greater in the LB group relative to the TP group (P = 0.0001). Oxidative DNA damage was significantly reduced in the livers of mice fed LB and TP diets relative to the control group. CONCLUSIONS: This preclinical trial suggests significant chemopreventive activity with a lycopene beadlet-enriched diet. The chemopreventive effects of lycopene from beadlets versus whole tomato products requires further testing in preclinical and clinical models of prostate cancer.

A versatile pitch tracking algorithm: from human speech to killer whale vocalizations.

In this article, a pitch tracking algorithm [named discrete logarithmic Fourier transformation-pitch detection algorithm (DLFT-PDA)], originally designed for human telephone speech, was modified for killer whale vocalizations. The multiple frequency components of some of these vocalizations demand a spectral (rather than temporal) approach to pitch tracking. The DLFT-PDA algorithm derives reliable estimations of pitch and the temporal change of pitch from the harmonic structure of the vocal signal. Scores from both estimations are combined in a dynamic programming search to find a smooth pitch track. The algorithm is capable of tracking killer whale calls that contain simultaneous low and high frequency components and compares favorably across most signal to noise ratio ranges to the peak-picking and sidewinder algorithms that have been used for tracking killer whale vocalizations previously.

Upside-down swimming behaviour of free-ranging narwhals.

BACKGROUND: Free-ranging narwhals (Monodon monoceros) were instrumented in Admiralty Inlet, Canada with both satellite tags to study migration and stock separation and short-term, high-resolution digital archival tags to explore diving and feeding behaviour. Three narwhals were equipped with an underwater camera pod (Crittercam), another individual was equipped with a digital archival tag (DTAG), and a fifth with both units during August 2003 and 2004. RESULTS: Crittercam footage indicated that of the combined 286 minutes of recordings, 12% of the time was spent along the bottom. When the bottom was visible in the camera footage, the narwhals were oriented upside-down 80% of the time (range: 61 100%). The DTAG data (14.6 hours of recordings) revealed that during time spent below the surface, the two tagged narwhals were supine an average of 13% (range: 9-18%) of the time. Roughly 70% of this time spent in a supine posture occurred during the descent. CONCLUSION: Possible reasons for this upside-down swimming behaviour are discussed. No preference for a clockwise or counter-clockwise direction of roll was observed, discounting the possibility that rolling movements contribute to the asymmetric left-handed helical turns of the tusk.

Stroke frequency, but not swimming speed, is related to body size in free-ranging seabirds, pinnipeds and cetaceans.

It is obvious, at least qualitatively, that small animals move their locomotory apparatus faster than large animals: small insects move their wings invisibly fast, while large birds flap their wings slowly. However, quantitative observations have been difficult to obtain from free-ranging swimming animals. We surveyed the swimming behaviour of animals ranging from 0.5 kg seabirds to 30 000 kg sperm whales using animal-borne accelerometers. Dominant stroke cycle frequencies of swimming specialist seabirds and marine mammals were proportional to mass(-0.29) (R(2)= 0.99, n = 17 groups), while propulsive swimming speeds of 1-2 m s(-1) were independent of body size. This scaling relationship, obtained from breath-hold divers expected to swim optimally to conserve oxygen, does not agree with recent theoretical predictions for optimal swimming. Seabirds that use their wings for both swimming and flying stroked at a lower frequency than other swimming specialists of the same size, suggesting a morphological trade-off with wing size and stroke frequency representing a compromise. In contrast, foot-propelled diving birds such as shags had similar stroke frequencies as other swimming specialists. These results suggest that muscle characteristics may constrain swimming during cruising travel, with convergence among diving specialists in the proportions and contraction rates of propulsive muscles.

Preliminary evidence for signature vocalizations among free-ranging narwhals (Monodon monoceros).

Animal signature vocalizations that are distinctive at the individual or group level can facilitate recognition between conspecifics and re-establish contact with an animal that has become separated from its associates. In this study, the vocal behavior of two free-ranging adult male narwhals (Monodon monoceros) in Admiralty Inlet, Baffin Island was recorded using digital archival tags. These recording instruments were deployed when the animals were caught and held onshore to attach satellite tags, a protocol that separated them from their groups. The signature content of two vocal categories was considered: (1) combined tonal/pulsed signals, which contained synchronous pulsatile and tonal content; (2) whistles, or frequency modulated tonal signals with harmonic energy. Nonparametric comparisons of the temporal and spectral features of each vocal class revealed significant differences between the two individuals. A separate, cross-correlation measure conducted on the whistles that accounted for overall contour shape and absolute frequency content confirmed greater interindividual compared to intraindividual differences. These data are consistent with the hypothesis that narwhals produce signature vocalizations that may facilitate their reunion with group members once they become separated, but additional data are required to demonstrate this claim more rigorously.

Bottlenose dolphin (Tursiops truncatus) calves appear to model their signature whistles on the signature whistles of community members.

Bottlenose dolphins are unusual among non-human mammals in their ability to learn new sounds. This study investigates the importance of vocal learning in the development of dolphin signature whistles and the influence of social interactions on that process. We used focal animal behavioral follows to observe six calves in Sarasota Bay, Fla., recording their social associations during their first summer, and their signature whistles during their second. The signature whistles of five calves were determined. Using dynamic time warping (DTW) of frequency contours, the calves' signature whistles were compared to the signature whistles of several sets of dolphins: their own associates, the other calves' associates, Tampa Bay dolphins, and captive dolphins. Whistles were considered similar if their DTW similarity score was greater than those of 95% of the whistle comparisons. Association was defined primarily in terms of time within 50 m of the mother/calf pair. On average, there were six dolphins with signature whistles similar to the signature whistles of each of the calves. These were significantly more likely to be Sarasota Bay resident dolphins than non-Sarasota dolphins, and (though not significantly) more likely to be dolphins that were within 50 m of the mother and calf less than 5% of the time. These results suggest that calves may model their signature whistles on the signature whistles of members of their community, possibly community members with whom they associate only rarely.

Call usage learning in gray seals (Halichoerus grypus).

Call usage learning can be demonstrated on 4 different levels: signaling on command, signaling and refraining from signaling on command, responding to a trained stimulus with a signal from a specific signal class, and responding to the playback of any untrained stimulus with one from the same signal class. Two young gray seals (Halichoerus grypus) were trained successfully to demonstrate the first 2 levels. They also learned to respond to 9 moan stimuli and 9 growl stimuli with vocalizations of the same class (Level 3). However, novel moan and growl stimuli tended to elicit growls. This casts doubt on the possibility that gray seals can reach the 4th level, but it demonstrates that they are capable of the first 3 levels of usage learning.

A gray seal's (Halichoerus grypus) responses to experimenter-given pointing and directional cues.

A gray seal (Halichoerus grypus) was trained to touch a target on its left or right by responding to pointing signals. The authors then tested whether the seal would be able to generalize spontaneously to altered signals. It responded correctly to center pointing and head turning, center upper body turning, and off-center pointing but not to head turning and eye movements alone. The seal also responded correctly to brief ipsilateral and contralateral points from center and lateral positions. Pointing gestures did not cause the seal to select an object placed centrally behind it. Like many animals in similar studies, this gray seal probably did not understand the referential character of these gestures but rather used signal generalization and experience from initial operant conditioning to solve these tasks.