Common dolphin whistle responses to experimental mid-frequency sonar.

Oceanic delphinids that occur in and around Navy operational areas are regularly exposed to intense military sonar broadcast within the frequency range of their hearing. However, empirically measuring the impact of sonar on the behavior of highly social, free-ranging dolphins is challenging. Additionally, baseline variability or the frequency of vocal state-switching among social oceanic dolphins during undisturbed conditions is lacking, making it difficult to attribute changes in vocal behavior to anthropogenic disturbance. Using a network of drifting acoustic buoys in controlled exposure experiments, we investigated the effects of mid-frequency (3-4 kHz) active sonar (MFAS) on whistle production in short-beaked (Delphinus delphis delphis) and long-beaked common dolphins (Delphinus delphis bairdii) in southern California. Given the complexity of acoustic behavior exhibited by these group-living animals, we conducted our response analysis over varying temporal windows (10 min- 5 s) to describe both longer-term and instantaneous changes in sound production. We found that common dolphins exhibited acute and pronounced changes in whistle rate in the 5 s following exposure to simulated Navy MFAS. This response was sustained throughout sequential MFAS exposures within experiments simulating operational conditions, suggesting that dolphins may not habituate to this disturbance. These results indicate that common dolphins exhibit brief yet clearly detectable acoustic responses to MFAS. They also highlight how variable temporal analysis windows-tuned to key aspects of baseline vocal behavior as well as experimental parameters related to MFAS exposure-enable the detection of behavioral responses. We suggest future work with oceanic delphinids explore baseline vocal rates a-priori and use information on the rate of change in vocal behavior to inform the analysis time window over which behavioral responses are measured.

Clinical and Economic Burden of Antibiotic Use Among Pediatric Patients With Varicella Infection in the Outpatient Setting: A Retrospective Cohort Analysis of Real-world Data in France.

BACKGROUND: Varicella infects 90% of children before age 9. Though varicella is self-limiting, its complications may require antibiotics, though how antibiotics are utilized for varicella in France is not well known. This study assessed antibiotic use and costs associated with varicella and its complications in pediatric patients managed in the outpatient setting in France. METHODS: A retrospective cohort study using the Cegedim Strategic Data-Longitudinal Patient Database, an electronic medical record database from general practitioners and office-based specialists in France, was conducted. Children <18 years old diagnosed with varicella between January 2014 and December 2018 with 3-month follow-up available were included. We used descriptive analysis to assess varicella-related complications, medication use, healthcare resource utilization and costs. RESULTS: Overall, 48,027 patients were diagnosed with varicella; 15.3% (n = 7369) had ≥1 varicella-related complication. Antibiotics were prescribed in up to 25.1% (n = 12,045/48,027) of cases with greater use in patients with complications (68.1%, n = 5018/7369) compared with those without (17.3%, n = 7027/40,658). Mean medication and outpatient varicella-related costs were €32.82 per patient with medications costing a mean of €5.84 per patient; antibiotics contributed ~23% to total costs annually. CONCLUSION: This study showed high antibiotic use for the management of varicella and its complications. A universal varicella vaccination program could be considered to alleviate complications and associated costs in France.

Behavioural responses of fin whales to military mid-frequency active sonar.

The effect of active sonars on marine mammal behaviour is a topic of considerable interest and scientific investigation. Some whales, including the largest species (blue whales, Balaenoptera musculus), can be impacted by mid-frequency (1-10 kHz) military sonars. Here we apply complementary experimental methods to provide the first experimentally controlled measurements of behavioural responses to military sonar and similar stimuli for a related endangered species, fin whales (Balaenoptera physalus). Analytical methods include: (i) principal component analysis paired with generalized additive mixed models; (ii) hidden Markov models; and (iii) structured expert elicitation using response severity metrics. These approaches provide complementary perspectives on the nature of potential changes within and across individuals. Behavioural changes were detected in five of 15 whales during controlled exposure experiments using mid-frequency active sonar or pseudorandom noise of similar frequency, duration and source and received level. No changes were detected during six control (no noise) sequences. Overall responses were more limited in occurrence, severity and duration than in blue whales and were less dependent upon contextual aspects of exposure and more contingent upon exposure received level. Quantifying the factors influencing marine mammal responses to sonar is critical in assessing and mitigating future impacts.

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients with Varicella Infection: a Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Patients <18 years old diagnosed with varicella during 2014-2018 with 3-month follow-up available were included. We described varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3-month post-diagnosis. RESULTS: We identified 114,578 children with a primary varicella diagnosis. 7.7% (n = 8,814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1%, n = 3,271). In all, 25.9% (n = 29,706/114,578) were prescribed antibiotics. A higher proportion of patients with complications than those without complications were prescribed antibiotics (64.3%, n = 5,668/8,814 vs. 22.7%, n = 24,038/105,764). Mean annualized varicella-related costs were £2,231,481 for the study cohort. Overall, antibiotic prescriptions cost ∼£262,007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs.

A Rare Case of Postoperative Encephalopathy in Twin.

The clinical picture of encephalopathy invites a broad differential with multiple etiologies. It is with judicious history, hospital course, lab testing, and imaging that the ultimate cause is identified. We present a unique case of identical twins who share a similar clinical presentation of postoperative encephalopathy. The striking similarities in both twins suggest a genetic component requiring further research to identify patients who are genetically predisposed.

Therapeutic inertia related to the injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes in UK primary care.

AIMS: To determine the extent of therapeutic inertia related to the weekly injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes (T2D) in the United Kingdom. MATERIALS AND METHODS: Adults with T2D who received their first primary care prescription of dulaglutide or semaglutide between January and July 2019 were identified from the UK Clinical Practice Research Datalink GOLD primary care database. Doses prescribed, glycated haemoglobin (HbA1c), body mass index (BMI) and concomitant T2D medications were assessed at first prescription and at 3, 6 and 9 months. RESULTS: Of the patients prescribed dulaglutide (N = 748; mean [SD] age 59.0 [11.2] years) and semaglutide (N = 437; mean [SD] age 58.4 [10.6] years), 93.0% and 89.0%, respectively, had an HbA1c level ≥7.5% (≥58.46 mmol/mol), and 56.4% and 54.9%, respectively, had an HbA1c level ≥9.0% (≥74.86 mmol/mol), at first prescription. At 6 to 9 months, 75.0% of those on dulaglutide 0.75 mg and 57.6% of those on semaglutide 0.25 mg or 0.5 mg had an HbA1c level ≥7.5% (≥58.46 mmol/mol). At 9 months, 21.9% of the dulaglutide cohort were on the suboptimal dose of 0.75 mg, and 46.1% of the semaglutide cohort were on the suboptimal doses of 0.25 mg or 0.5 mg. CONCLUSIONS: Multiple examples of therapeutic inertia were identified, including first prescription at HbA1c levels considerably above target and failure to escalate to optimal doses even with evidence of suboptimal metabolic control. A substantial proportion of patients therefore did not achieve optimal HbA1c targets.

Healthy Aging: Strategies to Slow the Process.

Aging, an ever-present process, is a part of every living organism's life cycle. Gerontology, the study of the biological, social, psychological aspects of aging, is a field that has been around since the 1930s, when the human inquiry into aging began to emerge. Aging can be characterized by the external changes, wrinkles, graying of the hair, among other changes, and lesser-seen but still important changes, presbycusis, arteriosclerosis, osteoporosis, cognitive decline, sarcopenia, and more. There is a strong drive to uncover as much as we can about the process of aging and the ways to delay its progression.

Merkel Cell Carcinoma of the Left Eyelid with Metastasis to the Left Submandibular Lymph Nodes: A Case Report and Brief Review.

Merkel cell carcinoma (MCC) is a cutaneous cancer often found on sun-exposed areas. MCC is rare but very often lethal making early diagnosis challenging although critical. There are only a few cases that have reported MCC of the eyelid making it often hard to identify in clinic. A 52-year-old woman with a firm nodule on the left eyelid was diagnosed with MCC that had also metastasized to a left submandibular lymph node. She underwent surgical excision of the mass and lymph node as well as parotid gland and neck dissection to rule out other metastases and then underwent radiation therapy. The aim of this study is to report a case of eyelid MCC with metastasis to a local lymph node to provide another example of the rare cancer in hopes that diagnosis and treatment options for MCC are more thoroughly studied and understood.

In-situ observations of the sensory hairs of Antarctic minke whales (Balaenoptera bonaerensis).

The sense of touch in the largest marine mammals is poorly understood. While mysticetes possess specialized sensory hairs that are present through adulthood, descriptions of these structures are based almost entirely on examination of tissues in post-mortem individuals. Sensory hairs have rarely been observed and described in living whales. We photographed Antarctic minke whales Balaenoptera bonaerensis in the Western Antarctic Peninsula and used high-resolution images to describe the number, distribution, orientation, and relative size of sensory hairs in freely swimming individuals. Sensory hairs were well developed. They were distributed on the tip of the lower jaw, the margins of the upper and lower jaw, and near the blowhole. Far fewer hairs were observed than reported for other mysticete species, including the related species Balaenoptera acutorostrata. Placement and apparent stiffness of sensory hairs within living tissue combined with observations and images of moving whales suggest these structures aid in detecting air and ice interfaces, and possibly, the boundaries of submerged prey fields.

Maternal responses to pup calls in a high-cost lactation species.

Bonding between mothers and their young is fundamental to mammalian reproductive behaviour and individual fitness. In social systems where the risk of confusing filial and non-filial offspring is high, mothers should demonstrate early, strong and consistent responses to their kin throughout the period of offspring dependence, irrespective of maternal traits. We tested this hypothesis through playback experiments in the northern elephant seal Mirounga angustirostris, a phocid species that breeds in high-density colonies. We found that mothers recognized their offspring throughout lactation and as early as 1-2 days after parturition. Measures of experience (age) and temperament (aggressivity) did not predict their response strength to filial playback treatments, nor did pup age or sex. Some mothers showed great consistency in behavioural responses throughout the lactation period, while others were less predictable. The strength of a female's response did not influence her pup's weaning weight; however, more consistent females weaned pups of higher mass. This is a rare demonstration of individual recognition among phocid mothers and their offspring, and suggests that consistency in maternal responsiveness may be an important social factor influencing the pup's growth and survival.

Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington's Disease PSC-Derived Striatal Neurons.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

Species information in whistle frequency modulation patterns of common dolphins.

The most flexible communication systems are those of open-ended vocal learners that can acquire new signals throughout their lifetimes. While acoustic signals carry information in general voice features that affect all of an individual's vocalizations, vocal learners can also introduce novel call types to their repertoires. Delphinids are known for using such learned call types in individual recognition, but their role in other contexts is less clear. We investigated the whistles of two closely related, sympatric common dolphin species, Delphinus delphis and Delphinus bairdii, to evaluate species differences in whistle contours. Acoustic recordings of single-species groups were obtained from the Southern California Bight. We used an unsupervised neural network to categorize whistles and compared the resulting whistle types between species. Of the whistle types recorded in more than one encounter, 169 were shared between species and 60 were species-specific (32 D. delphis types, 28 D. bairdii types). Delphinus delphis used 15 whistle types with an oscillatory frequency contour while only one such type was found in D. bairdii. Given the role of vocal learning in delphinid vocalizations, we argue that these differences in whistle production are probably culturally driven and could help facilitate species recognition between Delphinus species. This article is part of the theme issue 'Vocal learning in animals and humans'.

Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species.

BACKGROUND: Neuroinflammation may contribute to the pathogenesis of Huntington's disease, given evidence of activated microglia and elevated levels of inflammatory molecules in disease gene carriers, even those many years from symptom onset. We have shown previously that monocytes from Huntington's disease patients are hyper-reactive to stimulation in a manner dependent on their autonomous expression of the disease-causing mutant HTT protein. To date, however, whether human microglia are similarly hyper-responsive in a cell-autonomous manner has not been determined. METHODS: Microglial-like cells were derived from human pluripotent stem cells (PSCs) expressing mutant HTT containing varying polyglutamine lengths. These included lines that are otherwise isogenic, such that any observed differences can be attributed with certainty to the disease mutation itself. Analyses by quantitative PCR and immunofluorescence microscopy respectively of key genes and protein markers were undertaken to determine whether Huntington's disease PSCs differentiated normally to a microglial fate. The resultant cultures and their supernatants were then assessed by various biochemical assays and multiplex ELISAs for viability and responses to stimulation, including the release of pro-inflammatory cytokines and reactive oxygen species. Conditioned media were applied to PSC-derived striatal neurons, and vice versa, to determine the effects that the secretomes of each cell type might have on the other. RESULTS: Human PSCs generated microglia successfully irrespective of the expression of mutant HTT. These cells, however, were hyper-reactive to stimulation in the production of pro-inflammatory cytokines such as IL-6 and TNFα. They also released elevated levels of reactive oxygen species that have neurotoxic potential. Accompanying such phenotypes, human Huntington's disease PSC-derived microglia showed increased levels of apoptosis and were more susceptible to exogenous stress. Such stress appeared to be induced by supernatants from human PSC-derived striatal neurons expressing mutant HTT with a long polyglutamine tract. CONCLUSIONS: These studies show, for the first time, that human Huntington's disease PSC-derived microglia are hyper-reactive due to their autonomous expression of mutant HTT. This provides a cellular basis for the contribution that neuroinflammation might make to Huntington's disease pathogenesis.

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function In Vivo.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca2+ levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca2+ levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.SIGNIFICANCE STATEMENT Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system in vivo is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia in vivo.

Added sugars, saturated fat, and sodium intake from snacks among U.S. adolescents by eating location.

Snacking away from home is thought to contribute to excess intake of energy, added sugars, saturated fat, and sodium compared to snacking at home. Using data from the National Health and Nutrition Examination Survey 2009-2016, we examined associations between location of snack consumption (at home or away from home) and added sugars, saturated fat, and sodium intake from food and beverage snacks in U.S. adolescents aged 12-19. We also compared top snack contributors to intakes of these nutrients by location of consumption. Nutrient intake (added sugars, saturated fat, and sodium) from food and beverage snacks was estimated by the average intake from two 24-hour dietary recalls, and location of consumption for each snack was reported by participants as at home or away from home. Adjusted mixed effects models were performed to examine associations between nutrient intakes and the location of consumption. Adolescents (n = 3,869) had lower intakes of added sugars (-5.20 g/day), saturated fat (-2.06 g/day) and sodium (-170.15 mg/day) from food snacks consumed away from home compared to at home (p < 0.0001). Similarly, adolescents had lower intake of added sugars (-2.74 g/day), saturated fat (-0.32 g/day) and sodium (-16.04 mg/day) from beverage snacks consumed away from home compared to at home (p < 0.0001). The top contributors to the target nutrients were similar irrespective of location. Taken together, our results demonstrate that adolescents consumed more target nutrients from snacks at home than away from home. Larger snack portion sizes and higher frequency of snacking at home may explain these findings and requires further study.

Social exclusion affects working memory performance in young adolescent girls.

Adolescence has been proposed to be a sensitive period of social development, during which the social environment has a heightened effect on brain and behaviour. As such, negative social experiences, such as social exclusion, may have particularly detrimental effects on psychological well-being. However, little is known about how social exclusion affects cognitive performance during this time of life. Here, we compared the effects of exclusion between adolescence and adulthood. We recruited 98 females in three age groups: young adolescents (N = 36, aged 10.1-14.0), mid-adolescents (N = 35, aged 14.3-17.9) and adults (N = 27, aged 18.3-38.1). All age groups showed reductions in mood after exclusion, compared to inclusion, in a virtual ball-tossing game. Young adolescents also showed reduced verbal working memory accuracy following exclusion. There was no effect of exclusion on visuo-spatial working memory in any age group. These results suggest young adolescent girls' verbal working memory accuracy was affected by a short, virtual social exclusion experience. This highlights the importance of the social environment in adolescence and underlines the need to consider age differences in response to exclusion in the design and timing of social exclusion interventions in schools.

Behavioral responses of individual blue whales (Balaenoptera musculus) to mid-frequency military sonar.

This study measured the degree of behavioral responses in blue whales (Balaenoptera musculus) to controlled noise exposure off the southern California coast. High-resolution movement and passive acoustic data were obtained from non-invasive archival tags (n=42) whereas surface positions were obtained with visual focal follows. Controlled exposure experiments (CEEs) were used to obtain direct behavioral measurements before, during and after simulated and operational military mid-frequency active sonar (MFAS), pseudorandom noise (PRN) and controls (no noise exposure). For a subset of deep-feeding animals (n=21), active acoustic measurements of prey were obtained and used as contextual covariates in response analyses. To investigate potential behavioral changes within individuals as a function of controlled noise exposure conditions, two parallel analyses of time-series data for selected behavioral parameters (e.g. diving, horizontal movement and feeding) were conducted. This included expert scoring of responses according to a specified behavioral severity rating paradigm and quantitative change-point analyses using Mahalanobis distance statistics. Both methods identified clear changes in some conditions. More than 50% of blue whales in deep-feeding states responded during CEEs, whereas no changes in behavior were identified in shallow-feeding blue whales. Overall, responses were generally brief, of low to moderate severity, and highly dependent on exposure context such as behavioral state, source-to-whale horizontal range and prey availability. Response probability did not follow a simple exposure-response model based on received exposure level. These results, in combination with additional analytical methods to investigate different aspects of potential responses within and among individuals, provide a comprehensive evaluation of how free-ranging blue whales responded to mid-frequency military sonar.

High-amplitude vocalizations of male northern elephant seals and associated ambient noise on a breeding rookery.

Northern elephant seals (Mirounga angustirostris) are massive, land-breeding marine mammals that produce loud, stereotyped calls during annual breeding seasons. To determine vocalization source levels emitted by competing males on a mainland breeding rookery, aerial calls were measured on-axis at 1 m from adult males using three different sound pressure level metrics. Time-averaged (1 min) ambient noise was also measured under variable environmental and social conditions. Results indicate that male northern elephant seals emit high amplitude airborne calls with little variation in call amplitude. Mean source levels ranged from 98 to 114 dB re: 20 µPa [root-mean-square (rms) -fast], 102-116 dB re: 20 µPa (rms-impulse), and 120-131 dB re: 20 µPa (peak) and average standard deviations for all metrics were <2.3 dB. Further, these seal rookeries exhibit high variability in ambient noise (in terms of both spectrum and amplitude) from biotic and environmental sources. Finally, males sampled did not adjust call amplitude to compensate for higher background noise levels and thus did not exhibit a Lombard effect. These findings reinforce the view that the remarkable vocalizations of male northern elephant seals serve as rigid and powerful signals that convey individual identity within noisy breeding colonies rather than as honest indicators of size, status, or motivation.

The rise and fall of dialects in northern elephant seals.

Vocal dialects are fundamental to our understanding of the transmission of social behaviours between individuals and populations, however few accounts trace this phenomenon among mammals over time. Northern elephant seals (Mirounga angustirostris) provide a rare opportunity to examine the trajectory of dialects in a long-lived mammalian species. Dialects were first documented in the temporal patterns of the stereotyped vocal displays produced by breeding males at four sites in the North Pacific in 1968 and 1969, as the population recovered from extreme exploitation. We evaluated the longevity of these geographical differences by comparing these early recordings to calls recently recorded at these same locations. While the presence of vocal dialects in the original recordings was re-confirmed, geographical differences in vocal behaviour were not found at these breeding rookeries nearly 50 years later. Moreover, the calls of contemporary males displayed more structural complexity after approximately four generations, with substantial between-individual variation and call features not present in the historical data. In the absence of measurable genetic variation in this species-owing to an extreme population bottleneck-a combination of migration patterns and cultural mutation are proposed as factors influencing the fall of dialects and the dramatic increase in call diversity.