Adverse outcome pathway (AOP): α2u-globulin nephropathy and kidney tumors in male rats.

The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urgency, with the U.S. Environmental Protection Agency's directive to eliminate reliance on animal toxicity testing by 2035. To meet these needs, our goal was to elucidate the AOP for male-rat-specific kidney cancer. Male-rat-specific kidney tumors occur through the ability of structurally diverse substances to induce α2u-globulin nephropathy (α2u-N), a well-studied mode of action (MoA) not relevant in humans that results in kidney tumor formation in male rats. An accepted AOP may help facilitate the differentiation from other kidney tumors MoAs. Following identification and review of relevant in vitro and in vivo literature, both the MIE and subsequent KEs were identified. Based on the weight of evidence from the various resources, the confidence in this AOP is high. Uses of this AOP include hazard identification, development of in vitro assays to determine if the MoA is through α2u-N and not relevant to humans resulting in decreased use of animals, and regulatory applications.

Epidemiology, Management, and Outcomes of Accidental Hypothermia: A Multicenter Study of Regional Care.

BACKGROUND: Hypothermia is an uncommon, potentially life-threatening condition. We hypothesized (1) advanced rewarming techniques were more frequent with increased hypothermia severity, (2) active rewarming is increasingly performed with smaller intravascular catheters and decreased cardiopulmonary bypass, and (3) mortality was associated with age, hypothermia severity, and type. METHODS: Trauma patients with temperatures <35°C at 4 ACS-verified trauma centers in Wisconsin and Minnesota from 2006 to 2016 were reviewed. Statistical analysis included chi-square and Fisher's exact tests. A P value < .05 was considered significant. RESULTS: 337 patients met inclusion criteria; primary hypothermia was identified in 127 (38%), secondary in 113 (34%), and mixed primary/secondary in 96 (28%) patients. Hypothermia was mild in 69%, moderate in 26%, and severe in 5% of patients. Intravascular rewarming catheter was the most frequent advanced modality (2%), used increasingly since 2014. Advanced techniques were used for primary (12%) vs. secondary (0%) and mixed (5%) (P = .0002); overall use increased with hypothermia severity but varied by institution. Dysrhythmia, acute kidney injury, and frostbite risk worsened with hypothermia severity (P < .0001, P = .031, and P < .0001, respectively). Mortality was greatest in patients with mixed hypothermia (39%, P = .0002) and age >65 years (33%, P = .03). Thirty-day mortality rates were similar among severe, moderate, and mild hypothermia (P = .44). CONCLUSION: Advanced rewarming techniques were used more frequently in severe and primary hypothermia but varied among institutions. Advanced rewarming was less common in mixed hypothermia; mortality was highest in this subgroup. Reliance on smaller intravascular catheters for advanced rewarming increased over time. Given inconsistencies in management, implementation of guidelines for hypothermia management appears necessary.

Clinical features of scrupulosity: Associated symptoms and comorbidity.

OBJECTIVE: Scrupulosity is a manifestation of obsessive-compulsive disorder (OCD) characterized by religious or moral core fears. Clinicians often struggle to treat scrupulosity, which may be associated with several features known to predict poor treatment outcome. The purpose of this study was to examine these features in participants with scrupulous OCD, contamination OCD, and healthy controls. METHOD: A total of 68 participants (57.4% women, agemean = 34.01) completed diagnostic interviews, and measures of symptoms and quality-of-life. RESULTS: Relative to comparison groups, scrupulous participants had higher rates of obsessive-compulsive personality disorder, more severe schizotypal symptoms, and more severe symptoms of depression. In addition, OCD severity was strongly associated with poor insight in the scrupulous group. Both OCD groups reported poorer quality of life than did healthy controls. CONCLUSIONS: Clinicians working with scrupulous individuals may enhance the efficacy of treatment in this challenging population by assessing carefully for these features, and incorporating treatment elements that address them.

Career Satisfaction, Gender Bias, and Work-Life Balance: A Contemporary Assessment of General Surgeons.

OBJECTIVE: To identify factors and patterns of career and life satisfaction among general surgery residency graduates who completed all of their general surgery training after the implementation of duty hour restrictions. DESIGN: A 91-point electronic survey was distributed to assess experiences during medical school, residency, current surgical practice and work-life balance. Descriptive statistics and chi-square tests were completed. SETTING: Twenty-nine ACGME-accredited surgery residencies. PARTICIPANTS: Graduates of surgery residencies between 2008 and 2018. RESULTS: Three hundred thirty-six surgeons completed the survey (21% response rate); 42% (n = 141) were female. Seventy-nine percent (n = 81) of female and 92% (n = 138) of male surgeons reported overall career satisfaction (p = 0.004). Overall, 97% and 94% reported feeling competent to practice clinically and operate independently at the conclusion of their training. Thirty-four percent (n = 48) of women experienced gender bias/discrimination while on their medical school surgery rotation, compared to 6% (n = 12) of men (p < 0.001). Sixty-two percent (n = 63) of female surgeons reported gender bias in their practice, compared to 4% (n = 6) of men (p < 0.001). Of respondents with children, female surgeons were more likely to think having a child negatively affected their career advancement (p = 0.004), and 24% of female surgeons and 11% of male surgeons do not think having a family is supported by their practice (p = 0.02). If given the opportunity to choose a career again, 21% of female surgeons and 13% of male surgeons would choose a different profession (p = 0.13). CONCLUSIONS: General surgeons who completed their training after implementation of duty hour regulations are confident in their preparation for clinical practice. Female surgeons were less likely to be satisfied with their career and they report significantly more bias during their professional development and career. Work-life balance challenges were similar among men and women. Efforts are necessary to reduce gender bias across the spectrum of general surgeon training/career and to promote well-being among surgeons in practice.

Scrupulosity and contamination OCD are not associated with deficits in response inhibition.

BACKGROUND AND OBJECTIVES: Prior research has indicated a number of neuropsychological deficits in patients with OCD consistent with the cortico-striato-thalamo-cortical model of the disorder. Response inhibition (RI), defined as the inability to inhibit a prepotent response, has been identified as a possible candidate endophenotype for OCD. However, the results from previous studies of RI in OCD patients have been mixed, suggesting the possibility that some OCD dimensions may be associated with deficits in RI while others may not. The present study aimed to examine RI using a Go/No-Go (GNG) task in two OCD symptom dimensions, one of which, scrupulosity, has never been subject to neuropsychological investigation. METHODS: A total of 63 individuals, consisting of scrupulous OCD (n = 26), contamination OCD (n = 18) and non-psychiatric controls (n = 19) completed study measures. Controlling for depression symptoms, no significant performance differences were found between the groups on the GNG test, indicating no deficits in RI among contamination or scrupulous OCD. RESULTS: Results are consistent with several prior studies of RI in OCD that found no differences as compared to non-psychiatric controls, especially on GNG tests, and with more recent suggestions that RI may not constitute a clinical significant impaired domain in OCD. LIMITATIONS: Limitations included a primarily highly educated and Caucasian sample. CONCLUSIONS: Additional conclusions include careful consideration of the RI measures selected for future studies, as well as the need for further investigation into the neuropsychological and neurobiological nature of scrupulous OCD.

Mindfulness-based stress reduction for Tourette Syndrome and Chronic Tic Disorder: a pilot study.

OBJECTIVE: In this pilot study we sought to develop and test a modified form of mindfulness-based stress reduction (MBSR-tics) for the treatment of Tourette Syndrome (TS) and Chronic Tic Disorder (CTD). Our specific aims were: 1) To determine the feasibility and acceptability of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD and 2) To determine the efficacy of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD. METHODS: Eighteen individuals age 16-67 completed an uncontrolled open trial of MBSR-tics. The intervention consisted of 8 weekly 2-hour classes and one 4hour retreat in the fifth or sixth week of the program. Symptomatic assessments were performed at baseline, post-treatment, and one-month follow-up. RESULTS: MBSR-tics proved to be a feasible and acceptable intervention. It resulted in significant improvement in tic severity and tic-related impairment. 58.8% of subjects were deemed treatment responders. Therapeutic gains were maintained at 1-month follow-up. Improvements in tic severity were correlated with increases in self-reported levels of mindfulness. CONCLUSIONS: This small open pilot study provides preliminary support for the feasibility, acceptability, and efficacy of MBSR-tics for individuals 16 or older with TS or CTD. A larger randomized controlled trial with blind assessment is necessary to confirm these initial, promising findings. Trial Registration Partners Clinical Trials Registry Number 2011P000606 (clinicaltrials.partners.org).

Assessing squalor in hoarding: the Home Environment Index.

The current study examined a new measure of squalor associated with hoarding, the Home Environment Index (HEI). Participants (N = 793) were recruited from a large database of individuals who sought information about hoarding following national media appearances and consented to an internet study. Participants completed measures of hoarding and related psychopathology, including the HEI. The HEI showed good internal consistency and construct validity and reflected a single factor of home squalor (15 items). The HEI correlated positively with measures of hoarding and mood psychopathology. Recommendations for future modifications and further study are provided.

Multidecadal to multicentury scale collapses of Northern Hemisphere monsoons over the past millennium.

Late Holocene climate in western North America was punctuated by periods of extended aridity called megadroughts. These droughts have been linked to cool eastern tropical Pacific sea surface temperatures (SSTs). Here, we show both short-term and long-term climate variability over the last 1,500 y from annual band thickness and stable isotope speleothem data. Several megadroughts are evident, including a multicentury one, AD 1350-1650, herein referred to as Super Drought, which corresponds to the coldest period of the Little Ice Age. Synchronicity between southwestern North American, Chinese, and West African monsoon precipitation suggests the megadroughts were hemispheric in scale. Northern Hemisphere monsoon strength over the last millennium is positively correlated with Northern Hemisphere temperature and North Atlantic SST. The megadroughts are associated with cooler than average SST and Northern Hemisphere temperatures. Furthermore, the megadroughts, including the Super Drought, coincide with solar insolation minima, suggesting that solar forcing of sea surface and atmospheric temperatures may generate variations in the strength of Northern Hemisphere monsoons. Our findings seem to suggest stronger (wetter) Northern Hemisphere monsoons with increased warming.

The Relationship of Hoarding Symptoms to Schizotypal Personality and Cognitive Schemas in an Obsessive-Compulsive Disorder Sample.

This study examined hoarding symptoms and schizotypal personality traits (SPTs) in 38 patients with obsessive-compulsive disorder (OCD) and explored early maladaptive schemas (EMSs) as partial mediators between hoarding symptoms and schizotypal traits in OCD. Hoarding and symmetry/ordering symptoms were correlated with total schizotypal score on the Personality Disorder Questionnaire-4 (PDQ-4). Hoarding predicted the total number of schizotypal traits on the PDQ-4 after adjusting for symmetry/ordering symptoms. Schizotypal traits but not hoarding symptoms were significantly correlated with the social isolation and mistrust/abuse schemas. Schizotypal traits and hoarding were both associated with the emotional inhibition and emotional deprivation schemas, but neither of these mediated the relationship between schizotypal traits and hoarding. Clinical implications for understanding and treating hoarding and schizotypal personality in OCD are discussed.

Hoarding and the multi-faceted construct of impulsivity: a cross-cultural investigation.

The proposed hoarding disorder represents a serious psychiatric condition and considerable public health burden. Although tremendous strides have been made in understanding the phenomenology and treatment of this condition, many features regarding the etiology and nosology remain unclear. In particular, the association between impulsivity and hoarding, as well as the differential role of impulsivity versus compulsivity has yet to be fully considered. The current investigation sought to fill this gap in the literature by examining the relationship between hoarding and impulsivity across two independent, cross-cultural investigations. Two separate conceptualizations of the impulsivity construct were considered, including the Barratt Impulsivity Scale and the UPPS Impulsive Behavior Scale. Across Study 1 (US young adult sample; N = 372) and Study 2 (German young adult sample; N = 160) results revealed that hoarding was associated with greater rates of impulsivity, despite controlling for theoretically relevant covariates. More fined-grained analyses revealed a differential relationship with respect to the various facets of impulsivity, such that hoarding was most strongly linked with attentional and motor impulsivity, as well as urgency (i.e., impulsive behaviors in response to negative affect) and lack of perseverance. When considered simultaneously, both impulsivity and non-hoarding OCD symptoms explained unique variance in hoarding. The implications of impulsivity for hoarding are discussed from a classification perspective, as well as from a vulnerability standpoint.

Comprehension of self-report evidence-based measures of anxiety.

BACKGROUND: Given their applicability in diverse settings and for a wide range of purposes, the generalizability of self-report symptom measures is particularly important. An understudied factor in the development and validation of self-report measures is the degree to which they are difficult to comprehend. This study evaluated the difficulty of self-report measures of anxiety with respect to several domains, including formatting, length, and linguistic problems. METHODS: Ninety-two evidence based measures of anxiety were evaluated for comprehension level. RESULTS: The majority of anxiety measures included challenging elements of formatting, linguistic ability, and readability. Measures of obsessive-compulsive disorder were associated with the highest level of comprehension (i.e., greatest difficulty). CONCLUSIONS: The validity of self-report measures relies on the ability of respondents to understand the instructions and measure items. Factors related to the comprehension of self-report measures should be included among the basic psychometric properties in measure development and validation. Future research on the development of self-report measures that can be more broadly applicable across levels of education and literacy are of particular importance to research, clinical, and public health agendas.

Waitlist-controlled trial of cognitive behavior therapy for hoarding disorder.

OBJECTIVE: This study investigated a multicomponent cognitive behavioral treatment (CBT) for hoarding based on a model proposed by Frost and colleagues and manualized in Steketee and Frost (2007). METHOD: Participants with clinically significant hoarding were recruited from the community and a university-based anxiety clinic. Of the 46 patients randomly assigned to CBT or waitlist (WL), 40 completed the 12-week assessment and 36 completed 26 sessions. Treatment included education and case formulation, motivational interviewing, skills training for organizing and problem solving, direct exposure to nonacquiring and discarding, and cognitive therapy. Measures included the Saving Inventory-Revised (self-report), Hoarding Rating Scale-Interview, and measures of clinical global improvement. Between group repeated measures analyses using general linear modeling examined the effect of CBT versus WL on hoarding symptoms and moodstate after 12 weeks. Within group analyses examined pre-post effects for all CBT participants combined after 26 sessions. RESULTS: After 12 weeks, CBT participants benefited significantly more than WL patients on hoarding severity and mood with moderate effect sizes. After 26 sessions of CBT, participants showed significant reductions in hoarding symptoms with large effect sizes for most measures. At session 26, 71% of patients were considered improved on therapist clinical global improvement ratings and 81% of patients rated themselves improved; 41% of completers were clinically significantly improved. CONCLUSIONS: Multicomponent CBT was effective in treating hoarding. However, treatment refusal and compliance remain a concern, and further research with independent assessors is needed to establish treatment benefits and durability of gains.

Bacterial lipopolysaccharide enhances PDGF signaling and pulmonary fibrosis in rats exposed to carbon nanotubes.

Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later. Pulmonary fibrosis was observed 21 days after MWCNT exposure, but not with CB. LPS alone caused no fibrosis but enhanced MWCNT-induced fibrosis. LPS plus CB did not significantly increase fibrosis. MWCNT increased platelet-derived growth factor-AA (PDGF-AA), a major mediator of fibrosis. PDGF-AA production in response to MWCNT, but not CB, was synergistically enhanced by LPS. Immunostaining showed PDGF-AA in bronchiolar epithelial cells and macrophages. Since macrophages engulfed MWCNT, were positive for PDGF-AA, and mediate fibroblast responses, experiments were performed with rat lung macrophages (NR8383 cells) and rat lung fibroblasts in vitro. LPS exposure increased PDGF-A mRNA levels in NR8383 cells and enhanced MWCNT-induced PDGF-A mRNA levels. Moreover, LPS increased MWCNT- or CB-induced PDGF receptor-alpha (PDGF-Ralpha) mRNA in fibroblasts. Our data suggest that LPS exacerbates MWCNT-induced lung fibrosis by amplifying production of PDGF-AA in macrophages and epithelial cells, and by increasing PDGF-Ralpha on pulmonary fibroblasts. Our findings also suggest that individuals with pre-existing pulmonary inflammation are at greater risk for the potential adverse effects of MWCNT.

Inhaled carbon nanotubes reach the subpleural tissue in mice.

Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposure of 30 mg m(-3) for 6 h. Nanotubes were embedded in the subpleural wall and within subpleural macrophages. Mononuclear cell aggregates on the pleural surface increased in number and size after 1 day and nanotube-containing macrophages were observed within these foci. Subpleural fibrosis unique to this form of nanotubes increased after 2 and 6 weeks following inhalation. None of these effects was seen in mice that inhaled carbon black nanoparticles or a lower dose of nanotubes (1 mg m(-3)). This work suggests that minimizing inhalation of nanotubes during handling is prudent until further long-term assessments are conducted.

Group cognitive and behavioral treatment for compulsive hoarding: a preliminary trial.

BACKGROUND: Time-limited group cognitive behavioral treatments (GCBT) for obsessive-compulsive disorder have demonstrated improvement in target symptoms. One small sample study of GCBT specifically for hoarding problems also showed benefit. This study examines the efficacy of a specialized GCBT for compulsive hoarding on a larger sample. METHODS: Thirty-two clients diagnosed with hoarding participated in five groups. Four groups met once weekly for 2 hour over 16 weeks (n=27) and one group met for 20 weeks (n=5). All participants had two individual 90-min home sessions. Self-report assessments were completed at baseline, mid-treatment, and post-treatment about hoarding behavior and related symptoms (e.g., depression). The sample was predominantly female, White, highly educated, unemployed, and not partnered/married; mean age was 53. A majority was diagnosed with major depressive disorder and obsessive-compulsive personality disorder. RESULTS: Participants showed significant improvement from pre- to post-treatment on the Saving Inventory Revised, Saving Cognitions Inventory, Clutter Image Rating, and Clinical Global Severity. The most recent group (n=8) that used a more formalized treatment and research protocol improved significantly more than did earlier members. CONCLUSION: This study demonstrates the feasibility and modest success of GCBT methods in improving hoarding symptoms. Group treatment may be especially valuable because of its cost-effectiveness, greater client access to trained clinicians, and reduction in social isolation and stigma linked to this problem. Further research is needed to improve the efficacy of GCBT methods for hoarding and to examine durability of change, predictors of outcomes, and processes that influence change.

Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthma.

Carbon nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m(3)) or saline aerosol for 6 hours. Lung injury, inflammation, and fibrosis were examined by histopathology, clinical chemistry, ELISA, or RT-PCR for cytokines/chemokines, growth factors, and collagen at 1 and 14 days after inhalation. Inhaled MWCNT were distributed throughout the lung and found in macrophages by light microscopy, but were also evident in epithelial cells by electron microscopy. Quantitative morphometry showed significant airway fibrosis at 14 days in mice that received a combination of ovalbumin and MWCNT, but not in mice that received ovalbumin or MWCNT only. Ovalbumin-sensitized mice that did not inhale MWCNT had elevated levels IL-13 and transforming growth factor (TGF)-beta1 in lung lavage fluid, but not platelet-derived growth factor (PDGF)-AA. In contrast, unsensitized mice that inhaled MWCNT had elevated PDGF-AA, but not increased levels of TGF-beta1 and IL-13. This suggested that airway fibrosis resulting from combined ovalbumin sensitization and MWCNT inhalation requires PDGF, a potent fibroblast mitogen, and TGF-beta1, which stimulates collagen production. Combined ovalbumin sensitization and MWCNT inhalation also synergistically increased IL-5 mRNA levels, which could further contribute to airway fibrosis. These data indicate that inhaled MWCNT require pre-existing inflammation to cause airway fibrosis. Our findings suggest that individuals with pre-existing allergic inflammation may be susceptible to airway fibrosis from inhaled MWCNT.

An intramolecular upstream helix ensures the stability of a toxin-encoding RNA in Enterococcus faecalis.

The par stability determinant is required for the stable inheritance of the plasmid pAD1 in its native host, Enterococcus faecalis. It is the only antisense RNA-regulated addiction module identified to date in gram-positive bacteria. It encodes two small, convergently transcribed RNAs, RNA I and RNA II. RNA I encodes the Fst toxin and RNA II acts as the antitoxin by interacting with RNA I posttranscriptionally. As the toxin-encoding component of the system, it is important that RNA I is more stable than RNA II. This study reveals that a helix sequestering the 5' end of RNA I plays a crucial role in maintaining the stability of the RNA I. An adjacent structure previously determined to regulate Fst translation was not required to enhance stability. Results indicated that endoribonuclease J2 contributes significantly to the degradation of a mutant disrupting the upstream helix (UH) of RNA I in Bacillus subtilis. Finally, it was shown that interaction with RNA II stabilized the UH mutant of RNA I.

STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN-beta autocrine loop.

The inhalation of vanadium pentoxide (V(2)O(5)) results in bronchitis and airway fibrosis. The lung fibrotic response to V(2)O(5) partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V(2)O(5)-induced STAT-1 phosphorylation in lung fibroblasts requires H(2)O(2) and de novo protein synthesis. In this study, we identified IFN-beta as the protein that mediates STAT-1 activation by V(2)O(5) in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H(2)O(2) that drive IFN-beta gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-beta as well as an inhibitor of JAK. V(2)O(5) also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H(2)O(2)-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V(2)O(5)-induced IFN-beta mRNA levels and CXCL10 expression. IFN-alpha transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-beta and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V(2)O(5) injury.

Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators.

Skin cells (NHEK) take up untargeted quantum dots (QD) with surface polyethylene glycol (PEG), amines, and carboxylic acids, but the mechanisms are unknown. Time courses of QD-NHEK interactions were determined and effects of QD surface coating, temperature, culture medium supplements and inhibitors of the cell cycle and endocytosis identified. The magnitude of QD-NHEK interactions was coating dependent. Low-temperature or unsupplemented medium decreased QD-NHEK interactions. Biochemical inhibitors were identified that attenuate and potentiate QD-NHEK interactions. These results are important for understanding and controlling interactions of untargeted QD with cells.