Disturbance cues function as a background risk cue but not as an associative learning cue in tadpoles.

Chemical information has an important role in the sensory ecology of aquatic species. For aquatic prey, chemical cues are a vital source of information related to predator avoidance and risk assessment. For instance, alarm cues are released by prey that have been injured by predators. In addition to providing accurate information about current risk, repeated exposure to alarm cues can elicit a fear response to novel stimuli (neophobia) in prey. Another source of chemical information is disturbance cues, released by prey that have been disturbed or harassed (but not injured) by a predator. While disturbance cues have received much less attention than alarm cues, they appear to be useful as an early warning signal of predation risk and have the potential to be used as a priming cue for learning. In this study, we used wood frog (Lithobates sylvaticus) tadpoles to test whether repeated exposure to disturbance cues during the embryonic stage can induce neophobic behaviour. Three weeks following repeated exposure to disturbance cues, tadpoles showed reduced activity when exposed to a novel odour, but they no longer displayed an antipredator response to disturbance cues. In a second experiment, we found that tadpoles failed to learn that a novel odour was dangerous following a pairing with disturbance cues, whereas alarm cues facilitated such learning. Our results add to the growing body of information about disturbance cues and provide evidence of their function as an embryonic risk cue but not as an associative learning cue.

mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis.

INTRODUCTION: Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR-mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test. METHODS: Adults with hATTR in the NEURO-TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks. RESULTS: All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS-reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects. DISCUSSION: The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis.

INTRODUCTION: Hereditary transthyretin-mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO-TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. METHODS: Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. RESULTS: At 66 weeks, inotersen-treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. DISCUSSION: Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients' neuropathy experience in clinical practice.

Burden of hereditary transthyretin amyloidosis on quality of life.

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study we examine the impact of hATTR amyloidosis on quality of life (QOL). METHODS: Neuropathy-specific QOL, measured with the Norfolk QOL-Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36-item Short Form Health Survey version 2 (SF-36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases. RESULTS: Neuropathy-specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure. DISCUSSION: Patients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169-175, 2019.

Altering D1 receptor activity in the basolateral amygdala impairs fear suppression during a safety cue.

Accurate discrimination among cues signifying reward, danger or safety initiates the proper emotional response in order to guide behavior. Appropriate conditioned inhibition of fear in the presence of a safety cue would allow an organism to engage in reward seeking behaviors. There is currently little known about the mechanisms of reward, fear and safety cue discrimination and how a safety cue can inhibit fear and release reward seeking from inhibition. Here we assess reward, fear and safety cue learning together using a behavioral paradigm that has identified neurons that discriminate among these cues in the basolateral amygdala (BLA) (Sangha, Chadick, & Janak, 2013). Dopamine signaling in the BLA has been implicated in discriminatory reward learning, learned fear responses and fear extinction. We tested the hypothesis that D1 receptor activity will influence reward-fear-safety cue discrimination by using the D1 receptor agonist, SKF-3839, and antagonist, SCH-23390, either systemically or within the BLA during discrimination learning in male Long Evans rats. We show that both the agonist and antagonist interfered with fear suppression in the presence of the safety cue, when administered systemically or when infused directly into the BLA. This indicates that altering D1 receptor activity in the basolateral amygdala impairs fear suppression during a safety cue. Neither the agonist or antagonist had a consistent negative impact on discriminatory reward seeking when infused into the BLA. However, systemic administration of the D1 receptor agonist did reduce reward seeking behavior during a task that included fear and safety cues. We did not observe a negative impact on reward seeking during systemic administration of a D1 receptor agonist in a task that only included reward cue + sucrose and nonreward cue + no sucrose pairings. This indicates the impairments we saw with the systemically applied agonist in the safety-fear-reward cue discrimination task were more likely due to effects on fear and/or motivation rather than on cue discrimination. Together, our data indicate that altered dopamine D1 receptor activity in the BLA may be a potential mechanism that leads to the impairment in fear suppression to the safety signal seen with PTSD patients.

Optimizing outpatient total hip arthroplasty: perspectives of key stakeholders.

BACKGROUND: Advances in surgical techniques combined with multimodal analgesia and early rehabilitation have potentiated early mobilization in patients undergoing total hip arthroplasty (THA). Given an increasing push from patients to accelerate recovery and health care budgetary limitations, there has been growing interest in the implementation of outpatient THA in selected patients. Understanding the patient and primary caregiver experience of outpatient THA is important to optimize care. We aimed to gain insight into patient and caregiver perspectives regarding the perceived advantages and disadvantages of same-day discharge to identify areas of care that can be improved. METHOD: Using a qualitative descriptive approach, we conducted in-depth semistructured interviews with patient-primary caregiver dyads who experienced same-day discharge or standard care after primary THA with the direct anterior approach in 2016-2017. Two members of the research team coded the data independently, implementing a thematic and content analysis. RESULTS: Twenty-eight participants (16 same-day discharge, 12 standard care) were included. Both groups experienced high levels of satisfaction with their care pathway. Concerns and challenges identified in both groups pertained to mobility, pain, self-care and caregiver support. Challenges and concerns unique to same-day discharge were identified regarding expectations for recovery, medications and their impact on mobility, the timing of postoperative education and the availability of formal care. CONCLUSION: Outpatient THA can be implemented with high patient and caregiver satisfaction. Preoperative education, clarification of recovery processes and expectations, and proactively addressing concerns related to caregiving are important.

CONTEXTE: Les progrès des techniques chirurgicales, alliés à l'analgésie multimodale et à la réadaptation hâtive, ont potentialisé la mobilisation précoce des patients soumis à une intervention pour prothèse totale de la hanche (PTH). Compte tenu de la pression croissante venant des patients pour accélérer leur rétablissement et des contraintes budgétaires en santé, on s'intéresse de plus en plus à la PTH effectuée en externe chez certains patients. Pour optimiser les soins, il est important de comprendre l'expérience des patients et de leurs proches aidants relativement à la PTH effectuée en externe. Nous avons voulu cerner les points de vue des patients et des proches aidants au sujet des avantages et inconvénients perçus du congé le jour même, afin de déterminer quels éléments des soins gagneraient à être améliorés. MÉTHODES: À l'aide d'une approche qualitative descriptive, nous avons procédé à des entrevues semi-structurées approfondies avec des paires patients-proches aidants à qui on a offert soit le congé le jour même, soit les soins standards après une PTH primaire par approche antérieure directe en 2016-2017. Deux membres de l'équipe de recherche ont codé les données indépendamment, en procédant à une analyse par thèmes et par contenu. RÉSULTATS: Vingt-huit participants (16 ayant reçu leur congé le jour même et 12 soumis aux soins standards) ont été inclus. Les 2 groupes ont exprimé un degré élevé de satisfaction à l'endroit du déroulement de leurs soins. Les problèmes et les difficultés identifiés dans les 2 groupes concernaient la mobilité, la douleur, les soins personnels et le soutien aux proches aidants. Les difficultés ou problèmes particuliers aux cas de congé le jour même ont été associés aux attentes concernant le rétablissement, les médicaments et leur impact sur la mobilité, le moment de l'enseignement postopératoire et la disponibilité des soins standards. CONCLUSION: La PTH en externe peut être offerte et générer beaucoup de satisfaction chez les patients et leurs aidants. Il est important d'offrir un enseignement préopératoire, de clarifier le processus de rétablissement et les attentes et de répondre de manière proactive aux préoccupations exprimées relativement aux soins.

Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala.

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present. Since both the infralimbic cortex (IL) and amygdala have each been shown to be important for fear regulation to safety cues, we tested the necessity of specific IL projections to the basolateral amygdala (BLA) or central amygdala (CeA) during safety recall. Male Long Evans rats were used since prior work showed female Long Evans rats did not acquire the safety discrimination task used in this study. Here, we show the infralimbic projection to the central amygdala was necessary for suppressing fear cue-induced freezing in the presence of a learned safety cue, and the projection to the basolateral amygdala was not. The loss of discriminative fear regulation seen specifically during IL->CeA inhibition is similar to the behavioral disruption seen in PTSD individuals that fail to regulate fear in the presence of a safety cue.

Field experiments to assess passage of juvenile salmonids across beaver dams during low flow conditions in a tributary to the Klamath River, California, USA.

Across Eurasia and North America, beaver (Castor spp), their dams and their human-built analogues are becoming increasingly common restoration tools to facilitate recovery of streams and wetlands, providing a natural and cost-effective means of restoring dynamic fluvial ecosystems. Although the use of beaver ponds by numerous fish and wildlife species is well documented, debate continues as to the benefits of beaver dams, primarily because dams are perceived as barriers to fish movement, particularly migratory species such as salmonids. In this study, through a series of field experiments, we tested the ability of juvenile salmonids to cross constructed beaver dams (aka beaver dam analogues). Two species, coho salmon (Oncorhynchus kisutch) and steelhead trout (O. mykiss), were tracked using passive integrated transponder tags (PIT tags) as they crossed constructed beaver dam analogues. We found that when we tagged and moved these fishes from immediately upstream of the dams to immediately downstream of them, most were detected upstream within 36 hours of displacement. By the end of a 21-day field experiment, 91% of the displaced juvenile coho and 54% of the juvenile steelhead trout were detected on antennas upstream of the dams. In contrast, during the final week of the 21-day experiment, just 1 of 158 coho salmon and 6 of 40 (15%) of the steelhead trout were still detected on antennas in the release pool below the dams. A similar but shorter 4-day pilot experiment with only steelhead trout produced similar results. In contrast, in a non-displacement experiment, juveniles of both species that were captured, tagged and released in a pool 50 m below the dams showed little inclination to move upstream. Further, by measuring hydraulic conditions at the major flowpaths over and around the dams, we provide insight into low-flow conditions under which juvenile salmonids are able to cross these constructed beaver dams, and that multiple types of flowpaths may be beneficial towards assisting fish movement past instream restoration structures. Finally, we compared estimates of the number of juvenile salmonids using the pond habitat upstream of the dam relative to the number that the dam may have prevented from moving upstream. Upstream of the dams we found an abundance of juvenile salmonids and a several orders of magnitude difference in favor of the number of juveniles using the pond habitat upstream of the dam. In sum, our study suggests beaver dams, BDAs, and other channel spanning habitat features should be preserved and restored rather than removed as perceived obstructions to fish passage.

Natural infrastructure in dryland streams (NIDS) can establish regenerative wetland sinks that reverse desertification and strengthen climate resilience.

In this article we describe the natural hydrogeomorphological and biogeochemical cycles of dryland fluvial ecosystems that make them unique, yet vulnerable to land use activities and climate change. We introduce Natural Infrastructure in Dryland Streams (NIDS), which are structures naturally or anthropogenically created from earth, wood, debris, or rock that can restore implicit function of these systems. This manuscript further discusses the capability of and functional similarities between beaver dams and anthropogenic NIDS, documented by decades of scientific study. In addition, we present the novel, evidence-based finding that NIDS can create wetlands in water-scarce riparian zones, with soil organic carbon stock as much as 200 to 1400 Mg C/ha in the top meter of soil. We identify the key restorative action of NIDS, which is to slow the drainage of water from the landscape such that more of it can infiltrate and be used to facilitate natural physical, chemical, and biological processes in fluvial environments. Specifically, we assert that the rapid drainage of water from such environments can be reversed through the restoration of natural infrastructure that once existed. We then explore how NIDS can be used to restore the natural biogeochemical feedback loops in these systems. We provide examples of how NIDS have been used to restore such feedback loops, the lessons learned from installation of NIDS in the dryland streams of the southwestern United States, how such efforts might be scaled up, and what the implications are for mitigating climate change effects. Our synthesis portrays how restoration using NIDS can support adaptation to and protection from climate-related disturbances and stressors such as drought, water shortages, flooding, heatwaves, dust storms, wildfire, biodiversity losses, and food insecurity.

Effect of Osteochondroplasty on Time to Reoperation After Arthroscopic Management of Femoroacetabular Impingement: Analysis of a Randomized Controlled Trial.

Background: A subset of patients with femoroacetabular impingement (FAI) fail arthroscopic management. It is not clear which patients will fail surgical management; however, several surgical and patient factors, such as type of procedure and age, are thought to be important predictors. Purpose: This time-to-event analysis with a 27-month follow-up analysis compared the effect of (1) arthroscopic osteochondroplasty with or without labral repair versus (2) arthroscopic lavage with or without labral repair on the time to reoperation in adults aged 18 to 50 years with FAI. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Eligible participants had been randomized in a previous study trial to a treatment of arthroscopic osteochondroplasty or arthroscopic lavage with or without labral repair. Using the comprehensive data set from the Multinational Femoroacetabular Impingement Randomized controlled Trial, all reoperations until 27 months after surgery were identified. The analysis was conducted using a Cox proportional hazards model, with percentage of patients with a reoperation evaluated in a time-to-event analysis as the outcome. The independent variable was the procedure, with age and impingement subtype explored as potential covariates. The effects from the Cox model were expressed as the hazard ratio (HR). All tests were 2-sided, with an alpha level of .05. Results: A total of 108 patients in the osteochondroplasty group and 106 patients in the lavage group were included. The mean age of the patients included in the study was 36 ± 8.5 years. Overall, 27 incident reoperations were identified within the 27-month follow-up, with an incidence rate of 6 per 100 person-years. Within the osteochondroplasty group, 8 incident reoperations were identified (incidence rate, 3.4 per 100 person-years), while within the lavage group, 19 incident reoperations were identified (incidence rate, 8.7 per 100 person-years). The hazard of reoperation for patients undergoing osteochondroplasty was 40% of that of patients undergoing lavage (HR, 0.40 [95% CI, 0.17-0.91] P = .029). Conclusion: This study demonstrated that for adults between the ages of 18 and 50 years with FAI, arthroscopic osteochondroplasty was associated with a 2.5-fold decrease in the hazard of reoperation at any point in time compared with arthroscopic lavage. Registration: NCT01623843 (ClinicalTrials.gov identifier).

ABC of prescribing exercise as medicine: a narrative review of the experiences of general practitioners and patients.

BACKGROUND: Exercise prescribing can help patients to overcome physical inactivity, but its use in general practice is limited. The purpose of this narrative review was to investigate contemporaneous experiences of general practitioners and patients with exercise prescribing. METHOD: PubMed, Scopus, Science Direct and Cochrane reviews were reviewed using the terms 'exercise prescription', 'exercise prescribing', 'family practice', 'general practice', 'adults' and 'physical activity prescribing'. RESULTS: After screening by title, abstract and full paper, 23 studies were selected for inclusion. Qualitative, quantitative and mixed-methods studies revealed key experiences of general practitioners and patients. Barriers identified included: physician characteristics, patients' physical and psychosocial factors, systems and cultural failures, as well as ambiguity around exercise prescribing. We present a synthesis of the key strategies to overcome these using an ABC approach: A: assessment of physical activity: involves asking about physical activity, barriers and risks to undertaking an exercise prescription; B: brief intervention: advice, written prescription detailing frequency, intensity, timing and type of exercise; and C: continued support: providing ongoing monitoring, accountability and progression of the prescription. Multiple supports were identified: user-friendly resources, workshops for doctors, guidelines for specific illnesses and multimorbidity, electronic devices, health system support and collaboration with other healthcare and exercise professionals. DISCUSSION: This review has identified levers for facilitating exercise prescribing and adherence to it. The findings have been presented in an ABC format as a guide and support for general practitioners to prescribe exercise.

Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being.

BACKGROUND: Hereditary transthyretin (hATTR) amyloidosis is a rare, systemic, progressive, and life-threatening disease in which transthyretin proteins misfold and aggregate as insoluble amyloid deposits, disrupting nervous, cardiac, gastrointestinal, and other organ tissues. There are limited available data about the experience of patients living with hATTR amyloidosis. This study used a qualitative, non-interventional design to explore the humanistic burden of hATTR amyloidosis from the patient's perspective. RESULTS: Fourteen adults with hATTR amyloidosis, recruited from a patient advocacy group or an academic clinical center, participated in individual semi-structured interviews either in person or by telephone. Patients were asked to describe their experiences living with the condition, including symptoms and disease-related impacts on functioning and well-being, work, and activities of daily living (ADLs). Interviews were transcribed verbatim and analyzed for key concepts using a grounded theory approach. Patients described many symptoms of hATTR amyloidosis, particularly those associated with peripheral neuropathy such as pain, numbness, weakness, and paresthesia. Symptoms of autonomic neuropathy, such as gastrointestinal dysfunction, and symptoms related to cardiac dysfunction were also common. Worsening symptoms, especially those impacting patients' ability to walk or use their hands, often led to a loss of autonomy and an inability to work or perform ADLs. Disease-related disability also interfered with patients' participation in social activities, and contributed to feelings of fear, frustration, or sadness. CONCLUSIONS: The impacts of hATTR amyloidosis were profound for the patients interviewed for this study. They described a sense of loss as their condition progressed and impacted them physically, emotionally, and socially. Patients' reports of symptoms and impacts of hATTR amyloidosis illustrate the complex and varied manifestations of this disease. The progression of symptoms and increasing impacts of hATTR amyloidosis also highlight the need for an earlier diagnosis and effective clinical intervention to preserve patients' functioning and well-being.

The patient journey toward a diagnosis of hereditary transthyretin (ATTRv) amyloidosis.

BACKGROUND: Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study's objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis. METHODS: Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016-12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011-2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match. RESULTS: For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls. CONCLUSIONS: Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.

Osteochondroplasty and Labral Repair for the Treatment of Young Adults With Femoroacetabular Impingement: A Randomized Controlled Trial.

BACKGROUND: Femoroacetabular impingement (FAI) is a condition known to cause hip pain in young adults. PURPOSE: To evaluate the efficacy of the surgical correction of FAI via arthroscopic osteochondroplasty with or without labral repair compared with arthroscopic lavage of the hip joint with or without labral repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 220 male and female participants aged 18 to 50 years with nonarthritic FAI suitable for surgical treatment were recruited for the trial at 10 clinical centers in Canada, Finland, and Denmark between October 2012 and November 2017, of whom 214 were included in the final analysis. In the osteochondroplasty group, cam- and/or pincer-type lesions were resected using fluoroscopic guidance. In the lavage group, the joint was washed out with 3 L of normal saline. Surgeons were instructed to repair the labrum in both groups if it was mechanically unstable once probed, showing visible displacement or chondrolabral separation. The primary outcome was patient-reported pain (using the 100-point visual analog scale [VAS]) at 12 months. Secondary outcomes included hip function (Hip Outcome Score [HOS] and International Hip Outcome Tool), physical and mental health (12-Item Short Form Health Survey), and health utility (EuroQol-5 Dimensions) at 12 months as well as any reoperations and other hip-related adverse events at 24 months. RESULTS: At 12 months, there was no difference in pain (VAS) between the groups (mean difference [MD], 0.11 [95% CI, -7.22 to 7.45]; P = .98). Also, 88.3% (189/214) of participants had a labral tear, of which 60.3% were repaired. For the secondary outcomes, there were no significant differences between treatment groups, with the exception of the HOS activities of daily living domain in which lavage showed significant improvement compared with osteochondroplasty (MD, -5.03 [95% CI, -10.40 to -0.03]; P = .049). By 24 months, there were significantly fewer reoperations reported in the osteochondroplasty group (8/105) than the lavage group (19/104) (odds ratio, 0.37 [95% CI, 0.15-0.89]; P = .026). The primary reasons for a reoperation included hip pain (15/27; 55.6%) and a reinjury of the labrum (11/27; 40.7%). CONCLUSION: Both the osteochondroplasty and the lavage groups with or without labral repair for FAI had significantly improved pain or function significantly at 1 year. By 2 years, the reoperation rate was significantly lower in the osteochondroplasty group. REGISTRATION: NCT01623843 (ClinicalTrials.gov identifier).

Investigating the link between pulp mill effluent and endocrine disruption: attempts to explain the presence of intersex fish in the Wabigoon River, Ontario, Canada.

The ability of some pulp mill effluents (PME) to act as reproductive and endocrine disrupters in fish is well documented in the literature. However, changes are not always consistent with regard to species, gender, hormones, or reproductive effects. In the present study, the presence of the first intersexed fish that, to our knowledge, has been found in a Canadian river exposed to PME, is reported. A field survey of the Wabigoon River near Dryden, Ontario, in the fall of 2000 found intersexed walleye (Sander vitreus vitreus) with significantly altered hormone levels and reduced gonad size. The Wabigoon River receives discharge from a bleached kraft pulp and paper mill and a municipal wastewater (MWW) plant. It also has historical sediment contamination (wood fiber mats) contributing to extended periods of low dissolved oxygen under low flow, drought conditions. A mesocosm-based partial life cycle test exposing fathead minnows (Pimephales promelas) to reference water, 20% effluent volume to river volume (v/v), 40% (v/v), or 60% (v/v) PME as well as a field survey of the walleye in the Wabigoon River were conducted. The only change in our mesocosm exposure was a decrease in testosterone in males with increasing effluent concentration and vitellogenin induction in males exposed to 60% (v/v) effluent. These results did not reflect the magnitude of endocrine disruption seen in the wild fish survey. Several hypotheses that may explain these discrepancies are proposed. Specifically, evidence is offered from published studies indicating that either hypoxia or MWW, alone or in combination with PME, may explain the discrepancy between our field experiment and the wild fish survey. The present study illustrates the complexities of multistressor receiving environments and the need for the development of cumulative effects assessment approaches.

The Clinical and Economic Burden of Newly Diagnosed Hereditary Transthyretin (ATTRv) Amyloidosis: A Retrospective Analysis of Claims Data.

INTRODUCTION: Little is known about the burden of hereditary transthyretin (ATTRv) amyloidosis, a genetic, progressive, and fatal disease caused by extracellular deposition of transthyretin amyloid fibrils. The study's aim was to estimate costs and disease burden associated with ATTRv amyloidosis in a real-world setting. METHODS: Using IBM® MarketScan® Commercial and Medicare Supplemental data, we identified patients at least 18 years of age with newly diagnosed ATTRv amyloidosis. Diagnosis required at least one medical claim with relevant diagnosis code (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] 277.30-.31, 277.39; ICD-10-CM E85.0-.4, E85.89, E85.9) between January 1, 2014 and December 31, 2016, and at least one additional criterion occurring during study period (2013-2017): at least 15 days diflunisal use without more than a 30-day gap; liver transplant; or claim with codes E85.1 or E85.2. First diagnosis date was study index. Continuous enrollment 1-year pre-index (baseline) and post-index (follow-up) was required. Patients with baseline amyloidosis diagnosis were excluded. Outcomes of interest were comorbidities and 1-year follow-up healthcare utilization and costs (also reported quarterly). RESULTS: Among 185 qualifying patients, mean age was 59.2 years (standard deviation 15.2), 54.1% were female, and baseline Charlson comorbidity index was 2.2 (2.5). Neuropathy (30.3%), diabetes (27.0%), and cardiovascular-related comorbidities, including dyspnea (25.9%) and congestive heart failure (21.6%), were common during follow-up. Nearly a quarter of patients (24.9%) were hospitalized during follow-up. Most hospitalizations and emergency department visits occurred in the first quarter post-diagnosis (18.9%, 17.8%, respectively) and dropped in subsequent quarters. The annual mean total cost was $64,066, with inpatient services contributing the majority of the expenses ($34,461), followed by outpatient ($23,853), and then pharmacy ($5752). As with utilization, costs were highest in the first quarter post-diagnosis and dropped in subsequent quarters. CONCLUSION: Patients newly diagnosed with ATTRv amyloidosis have substantial healthcare utilization and costs in the first year, primarily the initial months, post-diagnosis. Further research should examine later costs associated with disease progression and end-of-life care.

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis.

OBJECTIVE: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. METHODS: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. RESULTS: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. CONCLUSION: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.

Development of working memory in the male adolescent rat.

Working memory develops over the course of adolescence, and neuroimaging studies find development-associated changes in the activity of prefrontal cortical brain regions. Establishment of a rodent model of working memory development would permit more comprehensive studies of the molecular and circuit basis for working memory development in health and disease. Thus, in this study, working memory performance was compared between adolescent and adult male Sprague-Dawley rats using an operant-based, delay-match-to-sample working memory task. Adolescent and adult rats showed similar rates of learning the task and similar performance at a low cognitive load (delays ≤ 6 s). However, when the cognitive load increased, adolescents exhibited impaired working memory performance relative to adults, until postnatal day 50 when performance was not significantly different. Despite evidence that cannabinoids disrupt working memory, we found no effect of acute treatment with the cannabinoid receptor agonist, WIN55212,2, at either age. Moreover, expression of glutamate and GABA receptor subunits was examined in the prelimbic and infralimbic prefrontal cortex across development. NMDA receptor subunit GluN2B expression significantly decreased with age in parallel with improvements in working memory. Thus, we show evidence that rats can be used as a model to study the molecular underpinnings of working memory development.

Hill-sachs "remplissage": an arthroscopic solution for the engaging hill-sachs lesion.

We present an arthroscopic technique used to treat traumatic shoulder instability in patients with glenoid bone loss and a large Hill-Sachs lesion. The procedure consists of an arthroscopic capsulotenodesis of the posterior capsule and infraspinatus tendon to fill the Hill-Sachs lesion. With the patient in the lateral decubitus position, a posterior portal is established at the lateral aspect of the convexity of the humeral head that is centered over the lesion. After anterior-inferior and anterior-superior portals have been established, the camera is placed in the anterior-superior portal. The Hill-Sachs lesion is freshened with a bur through the posterior portal. A cannula is inserted in the posterior portal through the deltoid but not through the infraspinatus or capsule, and an anchor is placed in the inferior aspect of the humeral lesion. A penetrating grasper is passed through the tendon and posterior capsule, 1 cm inferior to the initial portal entry site to pull 1 suture limb. A second anchor is placed superiorly, and 1 suture limb is similarly passed. The inferior suture is tied first with the knots remaining extra-articular, pulling the infraspinatus and capsule into the lesion. After completion, the Bankart lesion can then be repaired.

Modeling intrinsic potential for beaver (Castor canadensis) habitat to inform restoration and climate change adaptation.

Through their dam-building activities and subsequent water storage, beaver have the potential to restore riparian ecosystems and offset some of the predicted effects of climate change by modulating streamflow. Thus, it is not surprising that reintroducing beaver to watersheds from which they have been extirpated is an often-used restoration and climate-adaptation strategy. Identifying sites for reintroduction, however, requires detailed information about habitat factors-information that is not often available at broad spatial scales. Here we explore the potential for beaver relocation throughout the Snohomish River Basin in Washington, USA with a model that identifies some of the basic building blocks of beaver habitat suitability and does so by relying solely on remotely sensed data. More specifically, we developed a generalized intrinsic potential model that draws on remotely sensed measures of stream gradient, stream width, and valley width to identify where beaver could become established if suitable vegetation were to be present. Thus, the model serves as a preliminary screening tool that can be applied over relatively large extents. We applied the model to 5,019 stream km and assessed the ability of the model to correctly predict beaver habitat by surveying for beavers in 352 stream reaches. To further assess the potential for relocation, we assessed land ownership, use, and land cover in the landscape surrounding stream reaches with varying levels of intrinsic potential. Model results showed that 33% of streams had moderate or high intrinsic potential for beaver habitat. We found that no site that was classified as having low intrinsic potential had any sign of beavers and that beaver were absent from nearly three quarters of potentially suitable sites, indicating that there are factors preventing the local population from occupying these areas. Of the riparian areas around streams with high intrinsic potential for beaver, 38% are on public lands and 17% are on large tracts of privately-owned timber land. Thus, although there are a large number of areas that could be suitable for relocation and restoration using beavers, current land use patterns may substantially limit feasibility in these areas.