Search

INTRODUCTION: Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied. METHODS: Four databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. RESULTS: Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. CONCLUSIONS: Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.

Background and aimsThe expanded use of virtual care may worsen pre-existing disparities in use and delivery of end-of-life care among certain groups of people. We measured the use of virtual care in the last three months of life before and after the introduction of virtual care fee codes that funded care delivery at the start of COVID-19 on March 14, 2020, and identified changes in the characteristics of people using it.MethodsWe used linked clinical and administrative datasets to study use of virtual care in the last three months of life among 411,564 adults who died between January 25, 2018, and November 30, 2022. Modified Poisson regression was used to measure the association of the use of virtual care in the last three months of life with the pandemic study period and its association with each person- and physician-level factor.Results14,261 people (8%) used virtual care in the last three months of life before the pandemic, and 161,000 people (69%) used it during the pandemic (relative risk [RR] 8.76; 95% CI 8.48-9.05). Several individual patient characteristics were associated with statistically significant increases in the use of virtual care after March 14, 2020 (following the introduction of virtual care fee codes), compared to before such as among older adults, ethnic minorities, multiple chronic comorbid health conditions and higher frailty groups.ConclusionsThe introduction of new fee codes broadening technology and funding for end-of-life care at the start of pandemic combined with pandemic-related effects was associated with a substantial increase in the use of virtual care near the end of life among certain groups and a general leveling of pre-existing disparities in its use. Virtual end-of-life care delivery may strengthen person-centredness for individuals with limited ability to attend in-person appointments and by providers who may not have previously engaged in such care.

ObjectiveTo measure the association between types of serious illness and the use of different physician-delivered care models near the EOL during the COVID-19 pandemic.Design, setting and participantsPopulation-based cohort study using health administrative datasets in Ontario, Canada, for adults aged ≥18 years in their last 90 days of life who died of cancer or terminal noncancer illness and received physician-delivered care models near the end-of-life between March 14, 2020 and January 24, 2022.ExposureThe type of serious illness (cancer or terminal noncancer illness).Main outcomePhysician-delivered care models for adults in the last 90 days of life (exclusively virtual, exclusively home-based in-person, or mixed).ResultsThe study included 75,930 adults (median age 78 years, 49% female, cancer n = 58,894 [78%], noncancer illness n = 17,036 [22%]). A higher proportion of people with cancer (39.3%) received mixed model of care compared to those with noncancer illnesses (chronic organ failure 24.4%, dementia 37.9%, multimorbidity 28%). Compared to people with cancer, people with chronic organ failure (adjusted odds ratio [aOR], 1.61, 95% CI: 1.54 to 1.68) and those with multimorbidity ([aOR], 1.49, 95% CI: 1.39 to 1.59) had a higher odds of receiving virtual care than a mixed model of care. People with dementia had a higher odds of home-based in-person care than a mixed model of care ([aOR], 1.47, 95% CI 1.27, 1.71) and virtual care ([aOR], 1.40, 95% CI 1.20-1.62) compared to people with cancer.ConclusionA person's type of serious illness was associated with different care models near the end-of-life. This study demonstrates persistent disease-specific differences in care delivery or possibly the tailoring of models of care in the last 90 days of life based on a person's specific care needs.

IntroductionIn the context of collective efforts taken in Japan to control the spread of COVID-19, the state of emergency and social distancing have caused a negative impact on the mental health of all residents, including foreign communities in Japan. This study aimed to evaluate the level of anxiety and its associated factors among non-Japanese residents residing in Japan during the COVID-19 pandemic.MethodsA web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety-State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants.ResultsFrom January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (pConclusionOur study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.

IntroductionDepression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied.MethodsFour databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias.ResultsOf the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias.ConclusionsFuture research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.

Background and aims: The expanded use of virtual care may worsen pre-existing disparities in use and delivery of end-of-life care among certain groups of people. We measured the use of virtual care in the last three months of life before and after the introduction of virtual care fee codes that funded care delivery at the start of COVID-19 on March 14, 2020, and identified changes in the characteristics of people using it. Methods: We used linked clinical and administrative datasets to study use of virtual care in the last three months of life among 411,564 adults who died between January 25, 2018, and November 30, 2022. Modified Poisson regression was used to measure the association of the use of virtual care in the last three months of life with the pandemic study period and its association with each person- and physician-level factor. Results: 14,261 people (8%) used virtual care in the last three months of life before the pandemic, and 161,000 people (69%) used it during the pandemic (relative risk [RR] 8.76; 95% CI 8.48–9.05). Several individual patient characteristics were associated with statistically significant increases in the use of virtual care after March 14, 2020 (following the introduction of virtual care fee codes), compared to before such as among older adults, ethnic minorities, multiple chronic comorbid health conditions and higher frailty groups. Conclusions: The introduction of new fee codes broadening technology and funding for end-of-life care at the start of pandemic combined with pandemic-related effects was associated with a substantial increase in the use of virtual care near the end of life among certain groups and a general leveling of pre-existing disparities in its use. Virtual end-of-life care delivery may strengthen person-centredness for individuals with limited ability to attend in-person appointments and by providers who may not have previously engaged in such care. [ABSTRACT FROM AUTHOR]

Massive apoptosis of lymphocytes is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover, sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Thymic output and the numbers of naive and effector/memory CD4+ and CD8+ lymphocytes quickly recovered after sepsis. IL-7 treatment resulted in an accelerated recovery of CD8+ lymphocytes. Next generation sequencing revealed no significant narrowing of the T cell receptor repertoire 3.5 months after sepsis. In contrast, detailed functional analyses of T helper (Th)-cell responses towards a fungal antigen revealed a significant loss of Th cells. Whereas cytokine production was not impaired at the single cell level, the absolute number of Th cells specific for the fungal antigen was reduced. Our data indicate a clinically relevant loss of pathogen-specific T cell clones after sepsis. Given the small number of naive T lymphocytes specific for a given antigen, this decrement of T cell clones remains undetected even by sensitive methods such as deep sequencing. Taken together, our data are compatible with long lasting impairments in CD4+ T-cell responses after sepsis despite rapid recovery of T lymphocyte populations.

One of the defining features of the Anthropocene is eroding ecosystem services, decreases in biodiversity, and overall reductions in the abundance of once-common organisms, including many insects that play innumerable roles in natural communities and agricultural systems that support human society. It is now clear that the preservation of insects cannot rely solely on the legal protection of natural areas far removed from the densest areas of human habitation. Instead, a critical challenge moving forward is to intelligently manage areas that include intensively farmed landscapes, such as the Central Valley of California. Here we attempt to meet this challenge with a tool for modeling landscape connectivity for insects (with pollinators in particular in mind) that builds on available information including lethality of pesticides and expert opinion on insect movement. Despite the massive fragmentation of the Central Valley, we find that connectivity is possible, especially utilizing the restoration or improvement of agricultural margins, which (in their summed area) exceed natural areas. Our modeling approach is flexible and can be used to address a wide range of questions regarding both changes in land cover as well as changes in pesticide application rates. Finally, we highlight key steps that could be taken moving forward and the great many knowledge gaps that could be addressed in the field to improve future iterations of our modeling approach.

Background A bone-anchored prosthesis (BAP) eliminates the need for a conventional socket by attaching a prosthesis directly to the user’s skeleton. Currently, limited research addresses changes in gait mechanics post BAP implantation. Objective Examine changes in frontal plane movement patterns after BAP implantation. Methods Participants were individuals with unilateral transfemoral amputation (TFA) enrolled in the US Food and Drug Administration (FDA) Early Feasibility Study examining the Percutaneous Osseointegrated Prosthesis (POP). The participants completed overground gait assessments using their conventional socket and at 6-weeks, 12-weeks, 6-months, and 12-months following POP implantation. Statistical parameter mapping techniques were used in examining changes in frontal plane kinematics over the 12-months and differences with reference values for individuals without limb loss. Results Statistically significant deviations were found pre-implantation compared to reference values for hip and trunk angles during prosthetic limb stance phase, and for pelvis and trunk relative to the pelvis angles during prosthetic limb swing. At 6-weeks post-implantation, only the trunk angle demonstrated a statistically significant reduction in the percent of gait cycle with deviations relative to reference values. At 12-months post-implantation, results revealed frontal plane movements were no longer statistically different across the gait cycle for the trunk angle compared to reference values, and less of the gait cycle was statistically different compared to reference values for all other frontal plane patterns analyzed. No statistically significant within-participant differences were found for frontal plane movement patterns between pre-implantation and 6-weeks or 12-months post-implantation. Conclusions Deviations from reference values displayed prior to device implantation were reduced or eliminated 12-months post-implantation in all frontal plane patterns analyzed, while within-participant changes over the 12-month period did not reach statistical significance. Overall, the results suggest the transition to a BAP aided in normalizing gait patterns in a sample of relatively high functioning individuals with TFA.

Objective: To measure the association between types of serious illness and the use of different physician-delivered care models near the EOL during the COVID-19 pandemic. Design, setting and participants: Population-based cohort study using health administrative datasets in Ontario, Canada, for adults aged ≥18 years in their last 90 days of life who died of cancer or terminal noncancer illness and received physician-delivered care models near the end-of-life between March 14, 2020 and January 24, 2022. Exposure: The type of serious illness (cancer or terminal noncancer illness). Main outcome: Physician-delivered care models for adults in the last 90 days of life (exclusively virtual, exclusively home-based in-person, or mixed). Results: The study included 75,930 adults (median age 78 years, 49% female, cancer n = 58,894 [78%], noncancer illness n = 17,036 [22%]). A higher proportion of people with cancer (39.3%) received mixed model of care compared to those with noncancer illnesses (chronic organ failure 24.4%, dementia 37.9%, multimorbidity 28%). Compared to people with cancer, people with chronic organ failure (adjusted odds ratio [aOR], 1.61, 95% CI: 1.54 to 1.68) and those with multimorbidity ([aOR], 1.49, 95% CI: 1.39 to 1.59) had a higher odds of receiving virtual care than a mixed model of care. People with dementia had a higher odds of home-based in-person care than a mixed model of care ([aOR], 1.47, 95% CI 1.27, 1.71) and virtual care ([aOR], 1.40, 95% CI 1.20–1.62) compared to people with cancer. Conclusion: A person's type of serious illness was associated with different care models near the end-of-life. This study demonstrates persistent disease-specific differences in care delivery or possibly the tailoring of models of care in the last 90 days of life based on a person's specific care needs. [ABSTRACT FROM AUTHOR]

Fireflies are a family of charismatic beetles known for their bioluminescent signals. Recent anecdotal reports suggest that firefly populations in North America may be in decline. However, prior to this work, no studies have undertaken a systematic compilation of geographic distribution, habitat specificity, and threats facing North American fireflies. To better understand their extinction risks, we conducted baseline assessments according to the categories and criteria of the International Union for Conservation of Nature (IUCN) Red List for 132 species from the United States and Canada (approximately 79% of described species in the region). We found at least 18 species (14%) are threatened with extinction (e.g. categorized as Critically Endangered, Endangered, or Vulnerable) due to various pressures, including habitat loss, light pollution, and climate change (sea level rise and drought). In addition, more than half of the species (53%) could not be evaluated against the assessment criteria due to insufficient data, highlighting the need for further study. Future research and conservation efforts should prioritize monitoring and protecting populations of at-risk species, preserving and restoring habitat, gathering data on population trends, and filling critical information gaps for data deficient species suspected to be at risk.

BackgroundPsoriatic arthritis (PsA) is a progressive erosive joint disorder that causes functional impairment; therefore, early diagnosis and management are essential. This study evaluated the association between clinical specialty and the time to management in patients with PsA in Japan.MethodsThis was a subgroup analysis of a cross-sectional, multicenter, observational study that was conducted in 17 countries outside the United States, including 17 sites at 8 institutions in Japan, from June 2016 to October 2017. Data from consecutive patients (age ≥18 years) with a suspected or established diagnosis of PsA on a routine visit to a participating rheumatology/orthopedic or dermatology clinic in Japan were analyzed. The primary endpoints were time from onset of inflammatory musculoskeletal symptoms to PsA diagnosis, PsA diagnosis to first conventional synthetic disease-modifying antirheumatic drug (csDMARD), PsA diagnosis to first biologic DMARD (bDMARD), and first csDMARD to first bDMARD.ResultsOf 109 patients with a confirmed diagnosis of PsA, 39.4% (n = 43) and 60.6% (n = 66) were recruited by rheumatologists/orthopedists and dermatologists, respectively. Most patients were prescribed tumor necrosis factor inhibitors (58.7%) or methotrexate (56.0%). The mean duration from symptom onset to PsA diagnosis was significantly longer (p = 0.044) for patients treated by rheumatologists/orthopedists (70.6 months) than those treated by dermatologists (30.1 months). In the rheumatology/orthopedic and dermatology settings, the mean time from PsA diagnosis to first csDMARD administration was -0.9 and -2.9 months, and from PsA diagnosis to first bDMARD 21.4 and 14.9 months, respectively. The mean duration from administration of first csDMARD to first bDMARD was comparable in the rheumatology/orthopedic (31.8 months) and dermatology (31.5 months) settings.ConclusionsTreatment approach was slightly different between rheumatology/orthopedic and dermatology setting in clinical practice in Japan, suggesting that an integrated dermo-rheumatologic approach can optimize the management of patients with PsA.

BackgroundOcular inflammation causes significant visual morbidity in the United States, yet little is known about the epidemiology of infectious uveitis and scleritis. This study aims to evaluate the epidemiology of infectious uveitis/scleritis employing a large national medical claims database.MethodsThis was a retrospective, case-control study, employing Optum's de-identified Clinformatics® Data Mart Database, containing data from 21.5 million privately insured individuals with enrollment for at least 15 months within 2007-2015. Inclusion in the uveitis/scleritis sample required an index uveitis/scleritis diagnosis based on International Classification of Diseases, Ninth Revision (ICD-9) codes. Exclusion criteria included index date within 3 months after intraocular surgery. Rates for uveitis/scleritis were determined by anatomic site. Multivariable logistic regression analyses were performed to determine odds ratios for the incidence and prevalence of uveitis/scleritis by anatomic category.FindingsInfectious etiologies accounted for less than 20% of uveitis/scleritis, with mean rates of 18.9 (incidence) and 60.6 (prevalence) per 100,000 persons. The mean prevalences of infectious anterior, intermediate, posterior, panuveitis, and scleritis were 27.7, 0.17, 23.4, 4.4, and 4.6, per 100,000, respectively. Overall risk of prevalent infectious uveitis/scleritis increased with age (OR>3.3 for each decade over age 18, pConclusionsThe incidence and prevalence of infectious uveitis/scleritis in the United States were higher than previously reported estimates but remained lower than in developing countries. Rates varied by age, sex, race, and medical comorbidities, and may reflect differential susceptibility to various infectious agents with disparate geographic distributions within the United States.

We introduce and validate the use of commercially available human mobility datasets based on cell phone locations to estimate visitation to natural areas. By combining this data with on-the-ground observations of visitation to water recreation areas in New England, we fit a model to estimate daily visitation for four months to more than 500 sites. The results show the potential for this new big data source of human mobility to overcome limitations in traditional methods of estimating visitation and to provide consistent information at policy-relevant scales. However, the data providers' opaque and rapidly developing methods for processing locational information required a calibration and validation against data collected by traditional means to confidently reproduce the desired estimates of visitation. We found that with this calibration, the high-resolution information in both space and time provided by cell phone location-derived data creates opportunities for developing next-generation models of human interactions with the natural environment.

BACKGROUND:Nepal has achieved a significant reduction of TB incidence over the past decades. Nevertheless, TB patients continue to experience barriers in access, diagnosis and completion of the treatment. The main objective of this study was to explore the factors affecting the access to the health services, diagnosis and the treatment completion for TB patients in central and western Nepal. METHODS:Data were collected using in-depth interviews (IDI) with the TB patients (n = 4); Focus Group Discussions (FGDs) with TB suspected patients (n = 16); Semi Strucutred Interviews (SSIs) with health workers (n = 24) and traditional healers (n = 2); and FGDs with community members (n = 8). All data were audio recorded, transcribed and translated to English. All transcriptions underwent thematic analysis using qualitative data analysis software: Atlas.ti. RESULTS:Barriers to access to the health centre were the long distance, poor road conditions, and costs associated with travelling. In addition, lack of awareness of TB and its consequences, and the belief, prompted many respondents to visit traditional healers. Early diagnosis of TB was hindered by lack of trained health personnel to use the equipment, lack of equipment and irregular presence of health workers. Additional barriers that impeded the adherence and treatment completion were the need to visit health centre daily for DOTS treatment and associated constraints, complex treatment regimen, and the stigma. CONCLUSIONS:Barriers embedded in health services and care seekers' characteristics can be dealt by strengthening the peripheral health services. A continuous availability of (trained) human resources and equipment for diagnosis is critical. As well as increasing the awareness and collaborating with the traditional healers, health services utilization can be enhanced by compensating the costs associated with it, including the modification in current DOTS strategy by providing medicine for a longer term under the supervision of a family member, peer or a community volunteer.

Massive apoptosis of lymphocytes is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover, sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Thymic output and the numbers of naive and effector/memory CD4+ and CD8+ lymphocytes quickly recovered after sepsis. IL-7 treatment resulted in an accelerated recovery of CD8+ lymphocytes. Next generation sequencing revealed no significant narrowing of the T cell receptor repertoire 3.5 months after sepsis. In contrast, detailed functional analyses of T helper (Th)-cell responses towards a fungal antigen revealed a significant loss of Th cells. Whereas cytokine production was not impaired at the single cell level, the absolute number of Th cells specific for the fungal antigen was reduced. Our data indicate a clinically relevant loss of pathogen-specific T cell clones after sepsis. Given the small number of naive T lymphocytes specific for a given antigen, this decrement of T cell clones remains undetected even by sensitive methods such as deep sequencing. Taken together, our data are compatible with long lasting impairments in CD4+ T-cell responses after sepsis despite rapid recovery of T lymphocyte populations.

Squamous cell carcinoma-related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)-type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification.

The overall survival for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) remains low, with little progress made over decades. Cisplatin, most frequently used for HNSCC treatment, activates mitochondria-dependent apoptosis through the BCL-2 family proteins. We have previously demonstrated that the pro-apoptotic BH3-only protein, NOXA plays a critical role in this process. NOXA binds and inactivates anti-apoptotic MCL-1, while the BCL-2 inhibitor ABT-263 is capable of inactivating anti-apoptotic BCL-2 and BCL-XL. We hypothesized that combination of NOXA and ABT-263 treatment increases cell death by simultaneously inhibiting anti-apoptotic BCL-2 family proteins in HNSCC cells. Here, we demonstrated that combination of ectopic NOXA expression and ABT-263 enhanced apoptosis in p53-inactive, p53 wild-type, and human papillomavirus (HPV)-positive HNSCC cell lines. Furthermore, a retinoid derivative and an endoplasmic reticulum stress inducer, fenretinide, induced NOXA, and combination of fenretinide and ABT-263 strongly induced apoptosis in HNSCC cells regardless of the HPV or p53 statuses. We also found that MCL-1 and BCL-XL are the primary targets of apoptosis induced by the combinations. These results will develop novel and alternative therapeutic strategies to directly modify the cell death machinery in HNSCC.

We examined photic and ecological factors related to initiation of feeding by four sympatric primates in the rain forest of Amazonian Ecuador. With rare exceptions, morning activities of all taxa began only after the onset of nautical twilight, which occurred 47-48 min before sunrise. The larger spider and woolly monkeys, Ateles belzebuth and Lagothrix lagotricha poeppigii, left their sleeping trees before sunrise about half the time, while the smaller sakis and titi monkeys, Pithecia aequatorialis and Plecturocebus (formerly Callicebus) discolor, did not emerge until sunrise or later. None of the four taxa routinely began feeding before sunrise. Pithecia began feeding a median 2.17 h after sunrise, at least 0.8 h later than the median feeding times of the other three taxa. The early movement of Ateles and Lagothrix, and late initiation of feeding by Pithecia are consistent with temporal niche partitioning. Among most New World primate species, all males and many females, have dichromatic color vision, with only two cone photopigments, while some females are trichromats with three cone photopigments. Current evidence indicates that the dichromats have a foraging advantage in dim light, which could facilitate utilization of twilight periods and contribute to temporal niche partitioning. However, in our study, dichromatic males did not differentially exploit the dim light of twilight, and times of first feeding bouts of female Ateles and Lagothrix were similar to those of males. First feeding bouts followed a seasonal pattern, occurring latest in May-August, when ripe fruit abundance and ambient temperature were both relatively low. The most frugivorous taxon, Ateles, exhibited the greatest seasonality, initiating feeding 1.4 h later in May-August than in January-April. This pattern may imply a strategy of conserving energy when ripe fruit is scarcer, but starting earlier to compete successfully when fruit is more abundant. Lower temperatures were associated with later feeding of Ateles (by 26 min / °C) and perhaps Pithecia, but not Lagothrix or Plecturocebus. The potential for modification of temporal activity patterns and temporal niche partitioning by relatively small changes in temperature should be considered when predicting the effects of climate change.

Family health history (FHH) is a key predictor of health risk and is universally important in preventive care. However, patients may not be aware of the importance of FHH, and thus, may fail to accurately or completely share FHH with health providers, thereby limiting its utility. In this study, we conducted an online survey of 294 young adults and employees based at a US university setting regarding their knowledge, sharing behaviors, and perceived importance of FHH, and use of electronic clinical tools to document and update FHH. We also evaluated two educational interventions (written and video) to promote knowledge about FHH and its importance to health. We found that 93% of respondents were highly aware of their FHH, though only 39% reported collecting it and 4% using an online FHH tool. Seventy-three percent of respondents, particularly women, had shared FHH with their doctor when prompted, and fewer had shared it with family members. Participants in the video group were significantly more likely to understand the benefits of FHH than those in the written group (p = 0.02). In summary, educational resources, either video or written, will be helpful to promote FHH collection, sharing, and use of online FHH tools.

Estuarine food webs are generally considered to be supported by marine pelagic and benthic primary producers and by the import of dead organic matter from the open sea. Although estuaries receive considerable amounts of freshwater phytoplankton and organic compounds from adjacent rivers, the potential contribution of these living and dead matter to estuarine food webs is often assumed to be negligible and, therefore, not examined. Based on stable isotope analyses, we report the importance of freshwater suspended particulate organic matter (FW-SPOM) for fuelling estuarine food webs in comparison to estuarine SPOM and microphytobenthos. This previously neglected food source contributed 50-60% (annual average) of food intake of suspension-feeding bivalves such as cockles (Cerastoderma edule), mussels (Mytilus edulis) and Pacific oysters (Magallana gigas) at the Balgzand tidal flats, an estuarine site in the western Wadden Sea (12-32 psu). For these species, this proportion was particularly high in autumn during strong run-off of SPOM-rich freshwater, whilst estuarine SPOM (20%-25%) and microphytobenthos (15%-30%) were relatively important in summer when the freshwater run-off was very low. These findings have implications for our understanding of the trophic interactions within coastal food webs and for freshwater management of estuarine ecosystems.

Previous studies examining the other-race effect in school-age children mostly focused on recognition memory performance. Here we investigated perceptual discriminability for Asian-like versus Caucasian-like morph faces in school-age Taiwanese children and adults. One-hundred-and-two 5- to 12-year-old children and twenty-three adults performed a sequential same/different face matching task, where they viewed an Asian- or a Caucasian-parent face followed by either the same parent face or a different morphed face (containing 15%, 30%, 45%, or 60% contribution from the other parent face) and judged if the two faces looked the same. We computed the d' as the sensitivity index for each age groups. We also analyzed the group mean rejection rates as a function of the morph level and fitted with a cumulative normal distribution function. Results showed that the adults and the oldest 11-12-year-old children exhibited a greater sensitivity (d') and a smaller discrimination threshold (μ) in the Asian-parent condition than those in the Caucasian-parent condition, indicating the presence of an own-race advantage. On the contrary, 5- to 10-year-old children showed an equal sensitivity and similar discrimination thresholds for both conditions, indicating an absence of the own-race advantage. Moreover, a gradual development in enhancing the discriminability for the Asian-parent condition was observed from age 5 to 12; however, the progression in the Caucasian-parent condition was less apparent. In sum, our findings suggest that expertise in face processing may take the entire childhood to develop, and supports the perceptual learning view of the other-race effect-the own-race advantage seen in adulthood likely reflects a result of prolonged learning specific to faces most commonly seen in one's visual environment such as own-race faces.

Cassava is a staple food for people across sub-Saharan Africa. Over the last 20 years, there has been an increased frequency of outbreaks and crop damage in this region caused by the cassava-adapted Bemisia tabaci putative species. Little is known about when and why B. tabaci adults move and colonize new cassava crops, especially in farming systems that contain a mixture of cultivar types and plant ages. Here, we assessed experimentally whether the age and variety of cassava affected the density of B. tabaci. We also tested whether the age and variety of the source cassava field affected the variety preference of B. tabaci when they colonized new cassava plants. We placed uninfested potted "sentinel" plants of three cassava varieties (Nam 130, Nase 14, and Njule Red) in source fields containing one of two varieties (Nam 130 or Nase 14) and one of three age classes (young, medium, or old). After two weeks, the numbers of nymphs on the sentinel plants were used as a measure of colonization. Molecular identification revealed that the B. tabaci species was sub-Saharan Africa 1 (SSA1). We found a positive correlation between the density of nymphs on sentinel plants and the density of adults in the source field. The density of nymphs on the sentinels was not significantly related to the age of the source field. Bemisia tabaci adults did not preferentially colonize the sentinel plant of the same variety as the source field. There was a significant interactive effect, however, between the source and sentinel variety that may indicate variability in colonization. We conclude that managing cassava source fields to reduce B. tabaci abundance will be more effective than manipulating nearby varieties. We also suggest that planting a "whitefly sink" variety is unlikely to reduce B. tabaci SSA1 populations unless fields are managed to reduce B. tabaci densities using other integrative approaches.

BackgroundLeprosy remains a major stigmatizing condition. Stigma is a dynamic process resulting from the interaction between physical attributes caused by leprosy and the existing stereotypes in a community. Leprosy has pervasive impacts on all areas of life including psychosocial burden to an individual, social interaction, marriage, and employment. These impacts vary and are largely dependent on a particular culture and community. The main objective of this study was to explore the perceived stigma of leprosy amongst community members and health care providers in Lalitpur district of Nepal.MethodsA total of six focused group discussions (FGDs) with 43 participants from a community living close to Anandaban Leprosy Hospital and ten semi structured interviews (SSIs) with health care providers were conducted between October and December 2016. An interview guide was used for the FGDs and SSIs. All qualitative data were transcribed and translated into English and were thematically analyzed using Atlas.ti software.ResultsVisible deformities due to leprosy was one of the major contributing factors for stigma. Stigma was further exacerbated by an attitude to conceal the disease due to perceived fear of potential discrimination. While over the years, stigma was felt to be decreasing, various aspects of life were still affected by leprosy stigma including marriage, employment and social interaction. This was largely attributed to leprosy and its consequences, specifically the disability and deformity caused by leprosy.ConclusionLeprosy was still perceived to be feared and concealed because of potential discrimination, even within the community that was close to a long established leprosy hospital. Various aspects such as marriage, employment and social interaction were still affected by the stigma which was strongly associated with visible deformities. In addition to ongoing rehabilitation and stigma reduction programs, integrating strategies such as community engagement wherein community and leprosy affected person jointly take a role in stigma reduction programs can be helpful.

BACKGROUND:Medical Infrared Imaging (MII) is an investigative method that can be potentially used in emergency care to non-invasively detect thermal signatures associated with change in blood flow. We have developed a protocol for the use of MII in the Emergency Department (ED) and shown that it is feasible. To derive initial data for sample size calculations, we performed an exploratory study in patients with fever and sepsis. METHODS:The Leicester MII protocol was used to image the temperature patterns along the arm among three patient groups (control, fever and sepsis) of a total 56 patients. Anatomical markers were used to divide this gradient into upper arm, forearm, hand and finger regions. Variations in measurements within and between these regions were described. RESULTS:The thermal gradient down the arm was successfully extracted in all patients. The distribution of values in each region of the arm was described in control, fever and sepsis patients. There was a significant gradient between upper arm and finger in controls (2.75, p < 0.0001), but no gradient in fever (p = 0.944) or sepsis (p = 0.710). This was reflected in the finger/arm difference, which was of -2.74°C (±3.50) in controls, -0.39C (±2.48) in fever, and -1.80°C (±3.09) in sepsis. CONCLUSIONS:This study found different thermal gradients along the arm in control and febrile groups, and defined the degree of individual variation. It is likely that the difference between upper arm temperature and finger temperature (representing the temperature gradient down the arm) may be more useful than absolute measurements in future studies.

Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort.Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016.Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD-L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC.Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806).

The threat of anthropogenic climate change has seen a renewed focus on understanding contemporary patterns of species distribution. This is especially the case for the biota of tropical mountains, because tropical species often have particularly narrow elevational ranges and there are high levels of short-range endemism. Here we describe geographic patterns of ant diversity and distribution in the World Heritage-listed rainforests of the Australian Wet Tropics (AWT), revealing seasonal moisture stability to be an important environmental correlate of elevational patterns of species composition. We sampled ants in leaf litter, on the litter surface and on tree trunks at 26 sites from six subregions spanning five degrees of latitude and elevation ranges from 100-1,300 m. A total of 296 species from 63 genera were recorded. Species richness showed a slight peak at mid elevations, and did not vary significantly with latitude. Species composition varied substantially between subregions, and many species have highly localised distributions. There was very marked species turnover with elevation, with a particularly striking compositional disjunction between 600 m and 800 m at each subregion. This disjunction coincides with a strong environmental threshold of seasonal stability in moisture associated with cloud 'stripping'. Our study therefore provides further support for climatic stability as a potential mechanism underlying patterns of diversity. The average height of orographic cloud layers is predicted to rise under global warming, and associated shifts in seasonal moisture stability may exacerbate biotic change caused by rising temperature alone.

Moral judgments and moral emotions are a ubiquitous feature of social interactions. Humans decide quickly and intuitively whether an action is morally right or wrong. Schadenfreude and sympathy, as emotional reactions to the misfortunes of others, are prototypical moral emotions. So far, however, little evidence exists concerning children's understanding of schadenfreude. Within three studies, we investigated the experience of schadenfreude and sympathy among N = 364 children of different age groups. We interviewed the children while showing them picture stories. In the picture stories, we varied the behavior of the protagonist prior to a misfortune: (1) whether his behavior had been morally right or wrong, (2) whether the protagonist attained his goal, (3) whether the protagonist was responsible for the misfortune. In addition, in one study we varied (4) the emotional relationship of the interviewed children to the protagonist. Furthermore, we asked the children to decide whether they want to sit next to the protagonist or do him a favor. Results show that children experience sympathy as well as schadenfreude at the age of 4 years. Sympathy is more likely to arise when the protagonists of a story are likable, when these actors typically pursue morally positive goals, and if they are not responsible for their misfortune. In contrast, schadenfreude is more likely when the protagonist is disliked, when actors pursue immoral goals and if they are responsible for their misfortune. In addition, sympathy increases approach (helping behavior, sitting next to the agent and doing favors), whereas schadenfreude increases avoidance tendencies.

Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation.

PURPOSE:FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown. METHODS:Using multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed. RESULTS:FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3-6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months. CONCLUSION:In patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.

Prophylactic use of broad-spectrum insecticides is a common feature of broad-acre grains production systems around the world. Efforts to reduce pesticide use in these systems have the potential to deliver environmental benefits to large areas of agricultural land. However, research and extension initiatives aimed at decoupling pest management decisions from the simple act of applying a cheap insecticide have languished. This places farmers in a vulnerable position of high reliance on a few products that may lose their efficacy due to pests developing resistance, or be lost from use due to regulatory changes. The first step towards developing Integrated Pest Management (IPM) strategies involves an increased efficiency of pesticide inputs. Especially challenging is an understanding of when and where an insecticide application can be withheld without risking yield loss. Here, we quantify the effect of different pest management strategies on the abundance of pest and beneficial arthropods, crop damage and yield, across five sites that span the diversity of contexts in which grains crops are grown in southern Australia. Our results show that while greater insecticide use did reduce the abundance of many pests, this was not coupled with higher yields. Feeding damage by arthropod pests was seen in plots with lower insecticide use but this did not translate into yield losses. For canola, we found that plots that used insecticide seed treatments were most likely to deliver a yield benefit; however other insecticides appear to be unnecessary and economically costly. When considering wheat, none of the insecticide inputs provided an economically justifiable yield gain. These results indicate that there are opportunities for Australian grain growers to reduce insecticide inputs without risking yield loss in some seasons. We see this as the critical first step towards developing IPM practices that will be widely adopted across intensive production systems.

Agricultural landscapes can be characterized as a mosaic of habitat patches interspersed with hostile matrix, or as a gradient of patches ranging from suitable to unsuitable for different species. Arthropods moving through these landscapes encounter a range of edges, with different permeability. Patches of native vegetation in these landscapes may support natural enemies of crop pests by providing alternate hosts for parasitic wasps and/or acting as a source for predatory insects. We test this by quantifying species interactions and measuring movement across different edge-types. A high diversity of parasitoid species used hosts in the native vegetation patches, however we recorded few instances of the same parasitoid species using hosts in both the native vegetation and the crop (canola). However, we did find overall greater densities of parasitoids moving from native vegetation into the crop. Of the parasitoid groups examined, parasitoids of aphids (Braconidae: Aphidiinae) frequently moved from native vegetation into canola. In contrast, parasitoids of caterpillars (Braconidae: Microgastrinae) moved commonly from cereal fields into canola. Late season samples showed both aphids and parasitoids moving frequently out of native vegetation, in contrast predators moved less commonly from native vegetation (across the whole season). The season-long net advantage or disadvantage of native vegetation for pest control services is therefore difficult to evaluate. It appears that the different edge-types alter movement patterns of natural enemies more so than herbivorous pest species, and this may impact pest control services.

In bryophytes a morphological species concept is still most commonly employed, but delimitation of closely related species based on morphological characters is often difficult. Here we test morphological species circumscriptions in a species complex of the moss genus Racomitrium, the R. canescens complex, based on variable DNA sequence markers from the plastid (rps4-trnT-trnL region) and nuclear (nrITS) genomes. The extensive morphological variability within the complex has led to different opinions about the number of species and intraspecific taxa to be distinguished. Molecular phylogenetic reconstructions allowed to clearly distinguish all eight currently recognised species of the complex plus a ninth species that was inferred to belong to the complex in earlier molecular analyses. The taxonomic significance of intraspecific sequence variation is discussed. The present molecular data do not support the division of the R. canescens complex into two groups of species (subsections or sections). Most morphological characters, albeit being in part difficult to apply, are reliable for species identification in the R. canescens complex. However, misidentification of collections that were morphologically intermediate between species questioned the suitability of leaf shape as diagnostic character. Four partitions of the molecular markers (rps4-trnT, trnT-trnL, ITS1, ITS2) that could potentially be used for molecular species identification (DNA barcoding) performed almost equally well concerning amplification and sequencing success. Of these, ITS1 provided the highest species discrimination capacity and should be considered as a DNA barcoding marker for mosses, especially in complexes of closely related species. Molecular species identification should be complemented by redefining morphological characters, to develop a set of easy-to-use molecular and non-molecular identification tools for improving biodiversity assessments and ecological research including mosses.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery--TOM40--might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

We show how a climatic niche model can be used to describe the potential geographic distribution of a pest species with variable life-history, and illustrate how to estimate biogeographic pest threats that vary across space. The models were used to explore factors that affect pest risk (irrigation and presences of host plant). A combination of current distribution records and published experimental data were used to construct separate models for the asexual and sexual lineages of Rhopalosiphum padi (Linnaeus) (Hemiptera: Aphididae). The two models were combined with knowledge of host plant presence to classify the global pest risk posed by R. padi. Whilst R. padi has a relatively limited area in which sexual lineages can persist year round, a much larger area is suitable for transient sexual and asexual lineages to exist. The greatest risk of establishment of persistent sexual and asexual populations is in areas with warm temperate climates. At the global scale the models show very little difference in risk patterns between natural rainfall and irrigation scenarios, but in Australia, the amount of land suitable for persistent asexual and transient sexual populations decreases (by 20%) if drought stress is no longer alleviated by irrigation. This approach proved useful for modelling the potential distribution of a species that has a variable life-history. We were able to use the model outputs to examine factors such as irrigation practices and host plant presence that altered the nature (transient or permanent) and extent of pest risk. The composite niche maps indicate pest risk in terms that are useful to both biosecurity agencies and pest managers.

Myasthenia Gravis (MG) patients suffer from chronic fatigue of skeletal muscles, even after initiation of proper immunosuppressive medication. Since the localization of neuronal nitric oxide synthase (nNOS) at the muscle membrane is important for sustained muscle contraction, we here study the localization of nNOS in muscles from mice with acetylcholine receptor antibody seropositive (AChR+) experimental autoimmune MG (EAMG). EAMG was induced in 8 week-old male mice by immunization with AChRs purified from torpedo californica. Sham-injected wild type mice and mdx mice, a model for Duchenne muscular dystrophy, were used for comparison. At EAMG disease grade 3 (severe myasthenic weakness), the triceps, sternomastoid and masseter muscles were collected for analysis. Unlike in mdx muscles, total nNOS expression as well as the presence of its binding partner syntrophin α-1, were not altered in EAMG. Immunohistological and biochemical analysis showed that nNOS was lost from the muscle membrane and accumulated in the cytosol, which is likely the consequence of blocked neuromuscular transmission. Atrophy of all examined EAMG muscles were supported by up-regulated transcript levels of the atrogenes atrogin-1 and MuRF1, as well as MuRF1 protein, in combination with reduced muscle fiber diameters. We propose that loss of sarcolemmal nNOS provides an additional mechanism for the chronic muscle fatigue and secondary muscle atrophy in EAMG and MG.