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Huntington’s disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety. HD patients (n = 57) and at-risk individuals (n = 81) completed the Responses to Stress Questionnaire –Huntington’s Disease Version to assess HD-related stressors. Participants completed measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Patients endorsed a mean number of 5.05 stressors (SD = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p <  0.001) and anxiety symptoms (β=0.58, p <  0.001) in patients and at-risk individuals (β=0.35, p = 0.003 and β=0.32, p = 0.006, respectively). hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families.

Huntington’s disease (HD) presents patients and individuals at risk for HD with significant levels of stress. However, relatively little research has examined how individuals cope with stress related to the disease or the association of specific coping strategies with psychological symptoms. This study examined the ways in which HD patients and at-risk individuals cope with HD-related stress using a control-based model of coping and the association of coping strategies with symptoms of depression and anxiety. HD patients (n = 49) and at-risk individuals (n = 76) completed the Responses to Stress Questionnaire – Huntington’s Disease Version to assess coping strategies in response to HD-related stress, as well as standardized measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Patients and at-risk individuals reported using comparable levels of primary control coping, secondary control coping, and disengagement coping strategies. In linear regression analyses, only secondary control coping was significantly associated with lower depression (β= –0.62, p < 0.001) and anxiety (β= –0.59, p < 0.001) symptoms in patients and at-risk individuals (β= –0.55, p < 0.001 and β= –0.50, p < 0.001, respectively). Secondary control coping may be beneficial for both HD patients and at-risk individuals. Future research using the control-based model of coping in longitudinal studies with the HD population is needed, and future interventions could test the effects of cognitive reframing and acceptance as coping strategies for families affected by HD.

An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes.

Families in which a parent has Huntington’s disease (HD) are faced with significant stressors that can contribute to difficulties in communicating together about illness-related concerns. Family members who use more disengagement coping strategies, including denial and avoidance, to deal with illness-related stressors may have the greatest challenges to effective communication. The current study examined the associations of intrapersonal and interpersonal disengagement coping responses with observed and reported emotions of adolescents and young adults (AYA) at genetic risk for HD. Families included 42 AYA (n = 26 females) ages 10 to 34 (M = 19 years, 11 months; SD = 7 years, 6 months) and their parent with HD (n = 22 females, Mage = 46 years, 10 months; SD = 9 years, 2 months). Dyads participated in observations of communication and completed questionnaires about disengagement coping and internalizing symptoms. Disengagement coping of AYA was unrelated to their observed and reported emotional difficulties (intrapersonal coping). However, there was evidence for the importance of interpersonal disengagement coping, as AYA’s negative affect was observed and reported to be highest when bothAYA and their parents reported using high levels of avoidance, denial, and wishful thinking to cope with HD-related stress. The findings underscore the importance of a family-oriented approach to coping and communication in families affected by HD.

Purpose: Microneedling has been shown to enhance the efficacy of topical 5-fluorouracil (5-FU) for the treatment of dermatologic malignancies that along with our anecdotal clinical success of combination treatments for scar modification led the authors to investigate the effect of 5-FU and microneedling on wound healing. The current study evaluates the clinical and histological impact of topical 5-FU and microneedling therapy, separately, and in combination in a murine model.Methods: This is a randomized controlled trial in which 20 mice were randomized to 4 treatment groups: group 1 (n = 5) controls, group 2 (n = 5) microneedling alone, group 3 (n = 5) 5-FU alone, and group 4 (n = 5) combination 5-FU and microneedling. The interventions of interest were carried out on postoperative day 5, 10, 15, and 20 after wound induction. The clinical and histological wound appearance was graded by blinded oculoplastic surgeons and a blinded dermatopathologist, respectively. Statistical analysis was performed using a Kruskal-Wallis test with Dunn test for individual comparisons of treatment groups.Results: Blinded grading of the wound healing appearance at early, intermediate, and late healing time points demonstrated a statistically significant difference at the intermediate time point only. Histological analysis demonstrated a relative increase in epidermal thickness, dermal inflammation, and fibrosis in the combination treatment group. Statistically significant differences among the groups were identified in the degree of lymphocytic inflammation and for the amount of granulomatous inflammation.Discussion: This study was the first of its kind to investigate combination treatment with 5-FU and microneedling on a histopathologic level. In a murine model, this combination treatment resulted in increased degrees of wound inflammation and fibrosis relative to controls, and each treatment alone suggesting a histological basis that may relate to clinical impact, although future study in this area, to better understand the impact of these changes, is needed.Conclusion: Combination treatment with 5-FU and microneedling results in a histological increase in the degree of wound inflammation and fibrosis relative to controls and each treatment alone.

Concurrent anal, cervical and vulvovaginal screening in patients with a history of HPV-related gynecologic high-grade dysplasia or malignancy is feasible and acceptable to patients.

Little filtered cigars are tobacco products with many cigarette-like characteristics. However, despite cigars falling under the U.S. Food and Drug Administration regulatory authority, characterizing flavors, which are still allowed in little filtered cigars, and filter design may influence how people use the products and the resulting exposure to harmful and potentially harmful constituents. We estimated nicotine mouth level intake (MLI) from analyses of little cigar filter butt solanesol levels, brand characteristics, carbon monoxide boost, and puff volume in 48 dual cigarette/cigar users during two repeat bouts of ad lib smoking of three little filtered cigar brands. Mean nicotine MLI for the three brands was significantly different with Swisher Sweets (0.1% ventilation) Cherry at 1.20 mg nicotine, Cheyenne Menthol (1.5%) at 0.63 mg, and Santa Fe unflavored (49%) at 0.94 mg. The association between nicotine MLI and puff volume was the same between Cheyenne Menthol and Santa Fe unflavored. However, these were different from Swisher Sweets Cherry. At least five main factors─flavor, ventilation, filter design, nicotine delivery related to tar, and user puff volume─may directly or indirectly impact MLI and its association with other measures. We found that users of little filtered cigars that have different filter ventilation and flavor draw dissimilar amounts of nicotine from the product, which may be accompanied by differences in exposure to other harmful smoke constituents.

Background and objectivesThe clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers.MethodsTo assess cognitive symptoms in the developing brain, we administered assessments from the National Institutes of Health Toolbox Cognitive Battery, an age-appropriate cognitive assessment with population norms, to a cohort of children, adolescents and young adults with (gene-expanded; GE) and without (gene-not-expanded; GNE) the trinucleotide cytosine, adenine, guanine (CAG) expansion in the Huntingtin gene. These five assessments that focus on executive function are well validated and form a composite score, with population norms. We modelled these scores across age, and CAP score to estimate the slope of progression, comparing these results to motor symptoms.ResultsWe find significant deficits in the composite measure of executive function in GE compared with GNE participants. GE participant performance on working memory was significantly lower compared with GNE participants. Modelling these results over age suggests that these deficits occur as early as 18 years of age, long before motor manifestations of HD.ConclusionsThis work provides strong evidence that impairments in executive function occur as early as the second decade of life, well before anticipated motor onset. Future investigations should delineate whether these impairments in executive function are due to abnormalities in neurodevelopment or early sequelae of a neurodegenerative process.

Microneedle-delivered 5-Fluorouracil (5-FU) at a 50 mg/ml dose yields beneficial immunohistologic changes on postincisional wound healing in a murine model.

Identifying metabolites and delineating their immune-regulatory contribution in the tumor microenvironment is an area of intense study. Interrogating metabolites and metabolic networks among immune cell subsets and host cells from resected tissues and fluids of human patients presents a major challenge, owing to the specialized handling of samples for downstream metabolomics. To address this, we first outline the importance of collaborating with a biobank for coordinating and streamlining workflow for point of care, sample collection, processing and cryopreservation. After specimen collection, we describe our 60-min rapid bead-based cellular enrichment method that supports metabolite analysis between T cells and tumor cells by mass spectrometry. We also describe how the metabolic data can be complemented with metabolic profiling by flow cytometry. This protocol can serve as a foundation for interrogating the metabolism of cell subsets from primary human ovarian cancer.

Chronic heavy alcohol consumption is a major risk factor for the development of liver steatosis, fibrosis, and cirrhosis, but the mechanisms by which alcohol causes liver damage remain incompletely elucidated. This group has reported that α4 nicotinic acetylcholine receptors (α4 nAChRs) act as sensors for alcohol in lung cells. This study tested the hypothesis that α4 nAChRs mediate the effects of alcohol in the liver. Expression of acetylcholine receptor subunits in mouse liver was determined by RNA sequencing (RNA‐seq). α4 nAChR knockout (α4 KO) mice were generated in C57BL/6J mice by introducing a mutation encoding an early stop codon in exon 4 of Chrna4, the gene encoding the α4 subunit of the nAChR. The presence of the inactivating mutation was established by polymerase chain reaction and genomic sequencing, and the lack of α4 nAChR function was confirmed in primary fibroblasts isolated from the α4 KO mice. Wild‐type (WT) and α4 KO mice were fed the Lieber‐DeCarli diet (with 36% of calories from alcohol) or pair fed an isocaloric maltose‐dextrin control diet for a 6‐week period that included a ramping up phase of increasing dietary alcohol. Chrna4was the most abundantly expressed nAChR subunit gene in mouse livers. After 6 weeks of alcohol exposure, WT mice had elevated serum transaminases and their livers showed increased fat accumulation, decreased Sirt1 protein levels, and accumulation of markers of oxidative stress and inflammation including Cyp2E1, Nos2, Sod1, Slc7a11, TNFα, and PAI1. All these responses to alcohol were either absent or significantly attenuated in α4 KO animals. Together, these observations support the conclusion that activation of α4 nAChRs by alcohol or one of its metabolites is one of the initial events promoting the accumulation of excess fat and expression of inflammatory mediators. Thus, α4 nAChRs may represent viable targets for intervention in chronic alcohol‐related liver disease. Alcohol‐related liver disease is an important healthcare challenge. Herein, we show that mice lacking α4 nicotinic acetylcholine receptors (α4 KO mice) do not develop fatty liver like wildtype mice do when fed the Lieber‐DeCarli liquid alcohol diet for 6 weeks. Although signs of inflammation, oxidative stress, and cell death were mild in this model, the α4 KO mice were protected from these effects. Therefore, α4 nicotinic acetylcholine receptors may represent viable targets for intervention in chronic alcohol‐related liver disease.

Mainstream smoke yields of hydrogen cyanide (HCN) and three aromatic amines, 1-aminonaphthalene, 2-aminonaphthalene, and 4-aminobiphenyl, from 60 little cigar brands currently on the US market were measured for both International Organization for Standardization (ISO) and Canadian Intense (CI) smoking regimens. The smoke yields are compared with those from 50 cigarette products measured by Counts et al. of Philip Morris USA (PMUSA) in 2005 [Counts et al. Regul. Toxicol. Pharmacol.200541, 185−227] and 50 cigarette products measured by the Centers for Disease Control and Prevention (CDC) in cooperation with the Food and Drug Administration (FDA) in 2012 [Tynan et al. Consumption of Cigarettes and Combustible Tobacco: United States, 2000–2011. In Morbidity and Mortality Weekly Report; Centers for Disease Control and Prevention, 2012; 565−580]. For the little cigars, the average HCN yield with the ISO smoking regimen is 335 μg/cigar (range: 77–809 μg/cigar), which is 332% higher than the average of 50 PMUSA 2005 cigarettes and 243% higher than the average of 50 CDC/FDA 2012 cigarettes. For the CI smoking regimen, the average HCN yield is 619 μg/cigar (range: 464–1045 μg/cigar), which is 70.5% higher than the average of 50 PMUSA 2005 cigarettes and 69% higher than the average of the 50 CDC/FDA 2012 cigarettes. For aromatic amines, the average ISO smoking regimen smoke yields are 36.6 ng/cigar (range: 15.9–70.6 ng/cigar) for 1-aminonaphthalene, 24.6 ng/cigar (range: 12.3–36.7 ng/cigar) for 2-aminonaphthalene, and 5.6 ng/cigar (range: 2.3–17.2 ng/cigar) for 4-aminobiphenyl. The average ISO yields of aromatic amines from little cigars are 141% to 210% higher compared to the average yields of 50 PMUSA cigarettes. The average CI smoke regimen yields are 73.0 ng/cigar (range: 32.1–112.2 ng/cigar) for 1-aminonaphthalene, 45.2 ng/cigar (range: 24.6–74.8 ng/cigar) for 2-aminonaphthalene, and 12.7 ng/cigar (range: 5.5–37.5 ng/cigar) for 4-aminobiphenyl. The average CI aromatic amine yields are 143% to 220% higher compared to the average yields of 50 PMUSA cigarettes, almost identical to the relative yields under the ISO smoking regimen. Both HCN and aromatic amine yields are 1.5× to 3× higher for the tested little cigars than for the conventional cigarettes; however, there are notable differences in the relationships of these yields to certain product characteristics, such as weight, ventilation, and tobacco type. The higher smoke yields of these compounds from little cigars indicates that cigar smokers may be at risk of a higher exposure to HCN and aromatic amines on a per stick basis and thus increased health concerns.

Biobanks are a critical piece of Research Infrastructure (RI). However, biobanks need to accept the reality of a life cycle for RIs. Until recently, strategies to sustain biobanks have been commonly focused on ways to maintain current operational models. However, sustaining biobanks as they exist today may be increasingly challenging in the face of the disruption in health and research priorities caused by the COVID-19 pandemic. In this opinion article, we review the current and emerging future drivers of biobank value for their researchers, institutions, and funders, highlighting utilization and impact of research performed using the biobank as key measures of future value. While biobanks can only indirectly influence the specific impact of the research performed, they can transform themselves to more actively redefine utilization to their advantage. Utilization means more than the balance of samples and data in versus out. Utilization means redirecting expertise to best support end users, and importantly, closing the operating gap between biobanks and their end users who seek to find the right biospecimens and data to pursue their research. We discuss the specific role of locators (those created by public investment) in closing this gap and the need for additional tools for researchers, before and subsequent to connecting with locators. For the former, we specifically propose that more support is needed to assist researchers in the decision as to how to best obtain biospecimens and navigate the options as to whether finding existing biospecimens and data held by a biobank is the optimal solution for a given project, or whether the optimal solution is either contracting with a biobank to collect samples or creating a new biobank. We believe this type of biospecimen navigator platform will help to maximize utilization of current biobank resources, and also promote the services and expertise in biobanks to better serve researchers' needs.

Background:Over time, researchers' demand for increased quality and quantity of biospecimens has risen. However, quality is multifaceted, ranging from simple to complex, and comes at a cost. Therefore, to be sustainable and ensure optimal utilization of their resources (supply), biobanks must consider the trends in biospecimen use to predict the needs for future biospecimen quality (demand).Methods:An unbiased selection process was used to identify research articles from across the spectrum of cancer research from the PubMed database. A set of 225 articles utilizing human biospecimens were randomly selected for review (75 articles from each of three time intervals; 2000, 2010, 2020). Criteria for determining the source and complexity of quality of biospecimens were developed and overall concordance between two independent observers abstracting the data was then confirmed (k= 0.87) to validate the criteria.Results:We observed increased use of dual biospecimen formats (20%–36% of articles, p= 0.03), matched samples (16%–37% of articles, p= 0.0033), and biospecimens with associated outcomes data (20%–49%, p= 0.0002). In addition, the use of two or more cohorts increased over time (p= 0.03). The mechanism through which biospecimens were obtained also changed over time with an increase in the diversity of collection pathways used (p= 0.006).Conclusions:The complexity of biospecimens being used in cancer research and the diversity of collection pathways through which these are obtained has changed significantly. This observation is important for biobanks given that the cost to support the supply of biospecimens with complex extrinsic as opposed to simple intrinsic quality characteristics is greater. For biobanks to manage sustainability, optimize utilization, and meet changing research demand, they may need to adjust their operational models to better support the supply of these types of biospecimens.

Background:Tumor biobanks are a common research infrastructure. As a collection of biospecimens and annotated data collected to support a multitude of research projects, biobanks facilitate access to materials that are the critical fuel for the generation of data in up to 40% of cancer research publications. However, quantifying how to measure biobanks' impact and their value on the field of cancer research discoveries and findings, has not been well elucidated.Methods:We have used a qualitative case study approach to illustrate the impact of tumor biobanks. We assessed the impact of three research studies published between 2010 and 2012 that required easily accessible “classic” biobanks. Each study utilized preassembled collections of tumor biospecimens with associated patient outcomes data at the outset of the research project. We compared the resulting journal impact factor, altmetric and field-weighted citation impact factor scores for each article to a set of six “benchmark” articles that represent cancer research and treatment discoveries from the same time period and two sentinel scientific discovery articles.Results:We developed a value model using a literature search and design-thinking methodologies to illustrate the contributions of these “classic” model biobanks to these research studies. Assessment of the three example articles supported by biobanks demonstrates that the output can have impact that is comparable to the impact of a set of benchmark articles describing milestones in the field of cancer research and cancer care.Conclusions:These case studies illustrate the value of the sustained investment of funds, planning, time, and effort on the part of the biobanks before the conduct of the research study to be able to ultimately support high-value research. The “value” model will enable further discussion around impact and may be useful in better delineating qualitative metrics of biobank value in the future.

A method for determining the fraction of free-base nicotine (αfb) in electronic cigarette liquids (“e-liquids”) based on headspace solid-phase microextraction (h-SPME) is described. The free-base concentration ce,fb= αfbce,T, where ce,Tis the total (free-base + protonated) nicotine in the liquid. For gas/liquid equilibrium of the volatile free-base form, the headspace nicotine concentration is proportional to ce,fband thus also to αfb. Headspace nicotine is proportionally absorbed with an SPME fiber. The fiber is thermally desorbed in the heated inlet of a gas chromatograph coupled to a mass spectrometer: the desorbed nicotine is measured by gas chromatography–mass spectrometry. For a second h-SPME measurement, an adequate base is added to the sample vial to convert essentially all protonated nicotine to the free-base form (αfb→ 1.0). The ratio of the first h-SPME measurement to the second h-SPME measurement gives αfbin the initial sample. Using gaseous ammonia as the added base, the method was (1) verified using lab-prepared e-liquid solutions with known αfbvalues and (2) used to determine the αfbvalues for 18 commercial e-liquids. The measured αfbvalues ranged from 0.0 to 1.0. Increasing measurement error with decreasing αfbcaused modestly lower method precision at small αfb. Adding a liquid organic base may be more convenient than adding gaseous ammonia: one of the samples was examined using triethylamine as the added base; the measurements agreed well (with ammonia, 0.27 ± 0.01; with triethylamine, 0.26 ± 0.04). Other workers have proposed examining the nicotine protonation state in e-liquids using three steps: (1) 1:10 dilution with CO2-free water; (2) measurement of pH; and (3) calculation of the resulting values for αfb,w,1:10, the free-base fraction in the diluted mostly aqueous phase. As expected and verified here, because of the generally greater abilities of organic acids to protonate nicotine in water versusin an e-liquid phase, αfb,w,1:10values can be significantly less than actual e-liquid αfbvalues when αfbis not close to either 0 or 1.

Background:The permission to contact (PTC) platform is a useful mechanism to increase patient engagement and enrollment into biobanks. It provides biobanks with the ability to select specific patient cohorts and to complete consent to facilitate access to biospecimens and data. In this study, we evaluated consenting costs for a biobank to compile a research cohort based on utilizing a PTC platform to obtain consent as compared with utilizing a prospective consenting approach.Methods:In this study, we utilized a PTC platform to conduct an initial selection of potential participants for two breast cancer cohorts and to provide a “referral” to the biobank to recontact these patients to provide consent to access clinical archival biospecimens and associated data. We evaluated the effort, costs, and cohorts compiled by this approach to compare this mechanism with the alternative: compiling the same type of cohorts based on a classic biobank enrollment approach.Results:After initial diagnosis and provision of a PTC up to 12 years before, recontact was possible in 84 of 90 (74%) and 77 of 107 (72%) breast cancer patients for preinvasive (ductal carcinoma in situ[DCIS]) and invasive (triple-negative subtype) cancers. Of those recontacted, consent was completed in 42 of 84 (55%) DCIS patients and 48 of 107 (45%) triple negative breast cancer (TNBC) patients. The total cost of using PTC to recontact patients to compile these two consented cohorts was CAD $26.34 and CAD $20.11 per patient consent, respectively.Conclusions:We have demonstrated the feasibility of utilizing a PTC platform to obtain informed consent from patients for a specific study through referrals provided several years after initial PTC was provided. Depending on the existing biobank operational model and the efficiency of its processes for enrollment and obtaining broad informed consent, the implementation of a PTC platform may be an efficient and cost-effective complementary method for a biobank to enroll patients to develop criteria-specific cohorts to support research.

Two-tail ttest statistical analyses of International Organization for Standardization nonintense and Canadian Intense mainstream smoke yields of total particulate matter, tar, nicotine, and carbon monoxide from cigarettes show that mean quantities are generally higher for a linear smoking machine at a 95% confidence level but a rotary smoking machine has better precision. A novel “super pad” analysis concept combines four smaller filter pads from a linear smoking machine, resulting in increased mean constituent yields and reduced variability. Although measurement variability is still greater than that of rotary machines, super padding may be useful to reduce the variance caused by linear smoking machines.

Safer-at-home orders during the COVID-19 pandemic altered the structure of clinical care for Huntington’s disease (HD) patients. This shift provided an opportunity to identify limitations in the current healthcare infrastructure and how these may impact the health and well-being of persons with HD. The study objectives were to assess the feasibility of remote healthcare delivery in HD patients, to identify socioeconomic factors which may explain differences in feasibility and to evaluate the impact of safer-at-home orders on HD patient stress levels. This observational study of a clinical HD population during the ‘safer-at-home’ orders asked patients or caregivers about their current access to healthcare resources and patient stress levels. A chart review allowed for an assessment of socioeconomic status and characterization of HD severity. Two-hundred and twelve HD patients were contacted with 156 completing the survey. During safer-at-home orders, the majority of HD patients were able to obtain medications and see a physician; however, 25% of patients would not commit to regular telehealth visits, and less than 50% utilized an online healthcare platform. We found that 37% of participants were divorced/single, 39% had less than a high school diploma, and nearly 20% were uninsured or on low-income health insurance. Patient stress levels correlated with disease burden. A significant portion of HD participants were not willing to participate in telehealth services. Potential explanations for these limitations may include socioeconomic barriers and caregiving structure. These observations illustrate areas for clinical care improvement to address healthcare disparities in the HD community.

Background:Endoscopic dacryocystorhinostomy (endoDCR) has proven to be an effective minimally invasive surgical procedure for treatment of nasolacrimal duct obstruction. Post-surgical endonasal debridement has not yet been independently assessed for its impact on functional success. Methods:A retrospective review was performed of all patients who underwent endoDCR by an experienced oculofacial plastic surgeon over 7 years (2012-2019). Post-operative intranasal debridement was not routinely performed from March 2012 to February 2016. From March 2016 to June 2019, all patients underwent routine ipsilateral intranasal debridement at post-operative week 2. Surgical success was determined based upon subjective assessment of epiphora resolution at the patient’s final post-operative visit. Results:A total of 69 patients (88 surgeries) were included. Thirty-five patients had standard post-operative follow-up without debridement, whereas 34 underwent endonasal debridement at post-operative week 2. Demographics and follow-up were similar between the 2 groups. Functional success was achieved in 84.1% of patients without debridement, and in 97.7% with debridement (P= .058). Conclusion:This review demonstrates a trend toward improvement in the rate of surgical success of endoDCR when routine endonasal debridement was instituted 2 weeks following surgery. We believe that removal of nasal crusts, clots, and residual absorbable gelatin sponge at the osteotomy site improves tear outflow and reduces cicatricial healing enhancing patency of the surgically derived lacrimal-nasal fistula. We advocate for postoperative debridement in the perioperative management of endoDCR patients to optimize successful outcomes.

The mainstream smoke yields of five volatile organic compounds (VOCs) were determined from 60 commercial U.S. little cigar products under ISO 3308 and Canadian Intense (CI) smoking regimens on linear smoking machines using a gas sampling bag collection. The five VOCs, 1,3-butadiene, acrylonitrile, benzene, isoprene, and toluene were analyzed using an automated GC/MS analytical method validated for measuring various VOCs in mainstream smoke. The VOCs range in amounts from micrograms to milligrams per little cigar. VOC deliveries vary considerably among the little cigar products under the ISO smoking regimen primarily due to varying filter ventilation. Under the CI smoking regimen where filter ventilation is blocked, the delivery range narrows, although individual and total VOC yields are approximately 2 fold higher than those under the ISO smoking regimen. Correlation analysis reveals strong associations between acrylonitrile and 1,3-butadiene or toluene under the ISO smoking regimen. Compared to cigarettes, little cigars delivered substantially higher VOC mainstream smoke yields under both ISO and CI smoking regimens. Moreover, little cigar smoke also contains higher VOCs than cigarette smoke when adjusted for mass of tobacco.

The direct supraciliary brow lift is an effective procedure to treat brow ptosis, limited by risk of a cosmetically undesirable scar. We performed a comprehensive literature review of direct supraciliary brow lift techniques and provide a summary of the key considerations. The optimal direct brow lift is initiated with thoughtful incision design and a carefully beveled supraciliary incision. Subcutaneous tissue debulking and wound edge undermining optimize wound eversion and approximation. A layered meticulously executed skin closure is essential for optimal cosmesis. The senior author’s personal technique, incorporating these concepts, is described and illustrated. We reviewed 76 patients (141 brows) who underwent our refined technique. At the time of final follow-up visit (average 4.9 months), 72 patients (94.7%) reported complete satisfaction with results. Adverse outcomes were found in 4 patients (5.3%) and included transient paresthesias (n = 3) and hypertrophic scarring (n = 1). Postoperative care routinely included the use of topical steroids and additional treatment with microneedling and 5-fluorouracil in 2 patients (2.6%) to optimize healing. The direct supraciliary brow lift is a minimally invasive and effective procedure to correct brow ptosis and may yield excellent cosmesis when key principles are utilized.

Exposure to arsenic, a class I carcinogen, affects 200 million people globally. Skin is the major target organ, but the molecular etiology of arsenic-induced skin carcinogenesis remains unclear. Arsenite (As3+)-induced disruption of alternative splicing could be involved, but the mechanism is unknown. Zinc finger proteins play key roles in alternative splicing. As3+can displace zinc (Zn2+) from C3H1 and C4 zinc finger motifs (zfm’s), affecting protein function. ZRANB2, an alternative splicing regulator with two C4 zfm’s integral to its structure and splicing function, was chosen as a candidate for this study. We hypothesized that As3+could displace Zn2+from ZRANB2, altering its structure, expression, and splicing function. As3+/Zn2+binding and mutual displacement experiments were performed with synthetic apo-peptides corresponding to each ZRANB2 zfm, employing a combination of intrinsic fluorescence, ultraviolet spectrophotometry, zinc colorimetric assay, and liquid chromatography–tandem mass spectrometry. ZRANB2 expression in HaCaT cells acutely exposed to As3+(0 or 5 μM, 0–72 h; or 0–5 μM, 6 h) was examined by RT-qPCR and immunoblotting. ZRANB2-dependent splicing of TRA2B mRNA, a known ZRANB2 target, was monitored by reverse transcription–polymerase chain reaction. As3+bound to, as well as displaced Zn2+from, each zfm. Also, Zn2+displaced As3+from As3+-bound zfm’s acutely, albeit transiently. As3+exposure induced ZRANB2 protein expression between 3 and 24 h and at all exposures tested but not ZRANB2 mRNA expression. ZRANB2-directed TRA2B splicing was impaired between 3 and 24 h post-exposure. Furthermore, ZRANB2 splicing function was also compromised at all As3+exposures, starting at 100 nm. We conclude that As3+exposure displaces Zn2+from ZRANB2 zfm’s, changing its structure and compromising splicing of its targets, and increases ZRANB2 protein expression as a homeostatic response both at environmental/toxicological exposures and therapeutically relevant doses.

The promise of precision medicine will only be realized if the healthcare system adapts to meet some key infrastructure needs. Among these needs are adequate biobanking practices, capable of producing the biological samples and data that precision medicine relies upon in both the research and clinical phases. Within the research domain, there have been significant improvements to biobanking processes over the past two decades, driven by increased understanding of the impact of pre-analytical variability and the critical role of biospecimen and data quality. In the era of precision medicine, biobanking to support clinical needs has similar quality requirements. The extensive knowledge and resources that have been developed by the research biobanking community are available for adoption by clinical biobanking. The challenge and opportunity now presented to the healthcare system is to adopt or adapt these resources, for example, external biobanking standards and verification programs.

The current paper describes the PhenX (Phenotypes and eXposures) Toolkit Tobacco Regulatory Research Agent specialty area and the Agent Working Group’s (WG’s) 6-month consensus process to identify high-priority, scientifically supported measures for cross-study comparison and analysis. Eleven measures were selected for inclusion in the Toolkit. Eight of these are interviewer-administered or self-administered protocols: history of switching to lower tar and nicotine cigarettes, passive exposures to tobacco products, tobacco brand and variety (covering cigars, cigarettes and smokeless tobacco separately), tobacco product adulteration (vent-blocking or filter-blocking) and tobacco warning label exposure and recall. The remaining three protocols are either laboratory-based or visual inspection-based: measurement of nicotine content in smoked or smokeless tobacco products and the physical properties of these two classes of products. Supplemental protocols include a biomarker of exposure and smoking topography. The WG identified the lack of standard measurement protocols to assess subjective ratings of tobacco product flavours and their appeal to consumers as a major gap. As the characteristics of tobacco products that influence perception and use are tobacco regulatory research priorities, the reliable assessment of flavours remains an area requiring further development.

Fungicides protect winter wheat (Triticum aestivumL.) yield potential by managing foliar fungal diseases, but little information comparing one vs. two applications is available for the US southern Great Plains. Field experiments conducted from 2016–2018 at two Oklahoma locations (Apache and Stillwater) used two winter wheat cultivars (‘Gallagher’ and ‘Bentley’) and four fungicide application timings (control, Feekes 6, Feekes 9, and Feekes 6 + 9). Disease levels were highest during 2017 due to leaf rust. Dry conditions during 2018 limited disease development overall. Fungicide applications resulted in significantly higher yields in three of eight year × location × cultivar comparisons, all during 2017. The Feekes 6 + 9 treatment only showed the highest grain yield for the leaf rust‐susceptible cultivar Bentley at Stillwater that season. Partial profit was also examined by year, location, and cultivar using four fungicide cost scenarios at three grain sale prices. Only 22 of 96 comparisons showed significant positive partial profit from fungicide use, and all occurred at Stillwater during 2017. Two fungicide applications had the highest profit in 4 of the 22 comparisons for the cultivar Bentley. However, a single application of a low‐cost fungicide was most often among the highest profitable fungicide treatments, depending when higher disease levels were present. Partial profits from one and two fungicide applications were not significant or significantly negative when disease levels were low. Knowledge of cultivar disease susceptibility and disease scouting need to be considered to economically justify one or two fungicide applications in Oklahoma winter wheat.

Although 2-nitropropane is a potentially harmful compound present in cigarette smoke, there are few fully-validated, modern methods to quantitate it in mainstream cigarette smoke. We developed an isotope dilution gas chromatography-tandem mass spectrometry (ID-GC-MS/MS) method for the detection of 2-nitropropane in mainstream cigarette smoke. The vapor fraction of mainstream cigarette smoke was collected in inert polyvinyl fluoride gas sampling bags and extracted with hexanes containing isotopically labeled internal standard, then purified and concentrated via solid-phase extraction using a normal phase silica adsorbent and a 100% dichloromethane eluant. This method is sensitive enough to measure vapor phase 2-nitro-propane concentrations in the nanogram range, with a 19 ng per cigarette method limit of detection. Product variability estimated from the analysis of 15 cigarette products yielded relative standard deviations ranging from 5.4% to 15.7%, and estimates of precision from two quality control products yielded relative standard deviations of 9.49% and 14.9%. Under the Health Canada Intense smoking regimen, 2-nitropropane in machine-generated mainstream smoke from 15 cigarette products ranged from 98.3 to 363 ng per cigarette.

While several marine species exhibit biological rhythms of heart rate, gill ventilation, or locomotion, the relationship between these three measures in any species remains unexplored. The American horseshoe crab, Limulus polyphemusLinnaeus, 1758, expresses circalunidian locomotor rhythms and circadian eye sensitivity rhythms, but it is not clear if either heart and ventilation rates are controlled on a circadian, or circatidal basis or the nature of the relationship between these three measures. We aimed to determine the extent to which the heart and ventilation rates of L. polyphemusare coordinated with its endogenous rhythms of locomotion. We recorded rhythmic beating of the heart and movements of the gill plates in freely moving horseshoe crabs. Most individuals exhibited robust circatidal rhythms of locomotion, heart rate, and ventilation that were highly correlated with each other over three weeks of continuous recording. These results are the first showing long-term rhythms of all three measures in any marine species and suggest that heart rate and ventilation rhythms are coordinated in L. polyphemus, both with each other, and with locomotion, and thus are all modulated on a tidal basis.

Brown hyaenas Parahyaena brunneaare classified as ‘Near Threatened’. Although predominantly scavengers, they are frequently blamed for livestock depredations leading to persecution. Information on brown hyaena diets is important for understanding the degree of potential conflict with farming livelihoods and exploring diet variation across their range and how this might shift in response to land use change. Here we explore the diet of brown hyaena on a game reserve in the Limpopo Province, South Africa. We collected scats in 2013 (n= 55) and 2018 (n= 73) from Zingela Game Reserve to identify mammalian prey based on the cuticular scale imprints and cross-sectional appearance of hairs found in scat. Artiodactyls were most frequently consumed (total relative frequency of occurrence = 69.6%), dominated by common duiker Sylvicapra grimmiaand steenbok Raphicerus campestris. Smaller prey were also common with Rodentia appearing in 15.8% of scats, although for all prey items there was some variation between years. We found only one occurrence of a domestic species in scats (donkey Equus africanus). Set alongside other studies from across southern Africa the results illustrate that brown hyaena are flexible in their diet and that domestic animals generally only represent a very small proportion of their diet.

Globally, smokeless tobacco (ST) includes a wide array of chemically diverse products generally used in the oral cavity. Although ST has been widely investigated, this study was undertaken to determine the levels of sugars (mono- and di-saccharides), alditols, and humectants present in major ST categories/subcategories by using high performance liquid chromatography coupled with a triple quadrupole mass spectrometer (HPLC-MS/MS). The products studied included chewing tobacco (loose leaf, plug, twist), US moist snuff, Swedish snus, creamy snuff, dry snuff, dissolvable tobacco products, and tobacco-coated toothpicks. The highest mean sugar level was detected in chewing tobacco (9.3–27.5%, w/w), followed by dissolvable tobacco (2.1%); all other products were lower than 1%. Creamy snuff had the highest mean alditol levels (22.6%), followed by dissolvable tobacco (15.4%); all others had levels lower than 1%. The detected mean humectant levels ranged from non-detectable to 5.9%. This study demonstrates the broad chemical diversity among ST. This research may aid researchers and public health advocates investigating the exposures and risks of ST. [Beitr. Tabakforsch. Int. 28 (2019) 203–213]

Abstract:In this article, the author argues that the reason the problem of intentionality has persisted in contemporary analytic philosophy is because of an inadequate ontology of judgment and perception. This ontology stands in need of a corrective, so that we might render inferential practices continuous with other ways of relating to one's world. John McDowell has recognized this need, pointing out the almost incredible way in which, for instance, Robert Brandom claims that it is merely a contingent matter that discourse is bounded by perception and action, and that it could in principle exist without them. This isolative error common to contemporary analytic philosophy perpetuates the problem of intentionality and, therefore, agency. The article proceeds by showing how Alfred North Whitehead's aesthetic ontology can serve as a corrective. Whitehead's thought helps us to restore legitimacy to the idea of causal efficacy in perception—a crucial step toward a realist account of meaning and reference and, thereby, agency.

Leptospirosis is a globally important zoonotic disease, with complex exposure pathways that depend on interactions between human beings, animals, and the environment. Major drivers of outbreaks include flooding, urbanisation, poverty, and agricultural intensification. The intensity of these drivers and their relative importance vary between geographical areas; however, non-spatial regression methods are incapable of capturing the spatial variations. This study aimed to explore the use of geographically weighted logistic regression (GWLR) to provide insights into the ecoepidemiology of human leptospirosis in Fiji.

Supplemental Digital Content is available in the text.Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Abstract

Supplemental Digital Content is available in the text.Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.

This article presents the attitudinal response of rural villagers in Papua New Guinea to mobile telephony, based on a threshold study made during the early stages of its adoption. The research indicates that the introduction of mobile telecommunications has generally been viewed positively, with mobile phones affording social interaction with loved ones. Nonetheless, negative concerns have been strongly felt, notably financial costs and anxiety about mobile phones aiding in the coordination of extramarital liaisons and criminal activities. The communities investigated previously had scant access to modern communication technologies, some still using traditional means such as wooden slit drums, known locally as garamuts. The expansion of mobile network coverage has introduced into communal village life the capability to communicate dyadically and privately at a distance. Investigation into the adoption of mobile phones thus promotes understanding about traditional means of communication and notions of public and private interactions.

To directly compare perioperative morbidity and hospital stay after robotic-assisted staging and laparotomy in patients with early stage endometrial endometrioid adenocarcinoma and uterine weight under 480 g.

The article focuses on the legal development of the U.S. Bankruptcy Code of the Chapter 11 with the cases such as Baker Botts L.L.P. v. ASARCO LLC on administrative fees and expenses, U.S. Supreme Court's cases in Stern v. Marshall and Bank of America, N.A. v. Caulkett on lien stripping.

A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa.

The article focuses on several U.S. court cases related to the Chapter 11 of the U.S. Bankruptcy Code which include In re MPM Silicones on prepayment premiums, In re Sweports on the fees of professionals for declared debts of the estate, and the In re Motors Liquidation on security interest.

Arsenic is a widely distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet–environment interaction via a high-throughput metabolomics approach. GC×GC–TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice and point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease.

Most research on unburned tobacco has focused on the harmful chemicals associated with the tobacco itself. However, certain flavor additives in tobacco products can pose additional health risks. Flavors like camphor, coumarin, pulegone, eugenol, methyl salicylate, menthol and diphenyl ether have exhibited biological activity and/or toxicity in both lab animals and humans. This publication presents a new GC/MS method for the quantitation of ten flavor compounds (eucalyptol, camphor, menthol, pulegone, ethyl salicylate, methyl salicylate, cinnamaldehyde, eugenol, diphenyl ether and coumarin) in a variety of tobacco products, including smokeless products and cigar filler. Excellent linearity (>0.997), accuracy (93.9–106.6%) and precision (CV, 0.5–3.0%) were achieved for all flavor analytes measured. A summary of the concentrations of these flavors in selected international smokeless tobacco (SLT) products including zarda, quiwam, gutkha, and khaini varieties from Southeast Asia and snuff, clove cigarette filler and flavored cigar filler from the United States is reported. High concentrations of eugenol (2110 μg g−1), coumarin (439 μg g−1), camphor (1060 μg g−1) and diphenyl ether (4840 μg g−1) were found in selected products. Accurate identification and quantitation of potentially hazardous flavor compounds is important because they can exist in relatively high levels in some tobacco products, including international SLT products. We outline a versatile method which can be used to quantitate flavor compounds in multiple types of tobacco products.

Purpose:Facial nerve palsy may lead to significant functional facial and ocular morbidity. Soft tissue resuspension may improve both functional and aesthetic defects. We have adapted a minimally invasive midface suspension, which may be easily combined with routine paretic periocular rehabilitation to optimize outcomes. Methods: A retrospective review of patients with unilateral facial nerve palsy who underwent midcheek release and suture suspension simultaneous with periocular surgical rehabilitation at 2 surgical centers was performed. A temporal incision was made and dissection carried along the deep temporalis fascia to the lateral orbital rim. Dissection was continued subperiosteally along the anterior face of the maxilla to the piriform aperture. In severe cases, a second incision via superior buccal sulcus was utilized to maximize cheek soft tissue mobilization. Through 3 separate stab incisions along the nasolabial fold each end of a 0-0 permanent braided suture on a Keith needle was used to engage and elevate cheek soft tissues, secured at the deep temporalis fascia. Results: Seven patients (mean age 69 years) with unilateral facial nerve palsy and symptomatic facial droop underwent midface suture suspension simultaneous to eyelid reconstruction. With an average follow-up of 8.7 months, all patients demonstrated lasting improvement in facial asymmetry and reported satisfaction with their results. There were no significant postoperative complications. Conclusions: Midfacial static soft tissue resuspension is an effective minimally invasive surgical option for static facial rehabilitation in patients with facial nerve paralysis that can be performed at the time of periocular rehabilitation to enhance functional and aesthetic outcomes.

The U.S. Army Operating Room Specialist (68D) Course provides first class medical technician training to U.S. Army enlisted soldiers of the Army Medical Command. With a failure rate of approximately 12% over a 2-year period, this study was commissioned to determine whether the Armed Services Vocational Aptitude Battery (ASVAB) skilled technical (ST) Score served as a reliable predictor for successful first-attempt completion of the 68D course. A sample size of 373 was analyzed via a multivariate binary logistic regression model with 6 distinct independent variables. This study found that the ASVAB ST score, gender, and rank were predictors to first-attempt successful completion of the 68D training program. Specifically, students with an ST score 10 points higher than their peers were 5 times more likely to graduate. In addition, females were 2.5 times more likely to succeed than males and Army Privates (E2) were 3.2 times more likely than Privates (El). Specialists, Corporals (E4), Sergeants (E5), and Staff Sergeants (E6) combined, were 34 times more likely to succeed than Els. Although further study may be warranted, increasing the minimum ST score requirement in the admission guidelines and/or specific preventive assistance for lower-ranked students may decrease the first-attempt failure rate.

The aim of this trial was to undertake an assessment of ballistic neck collars to assess comfort and potential military performance restriction. Neck collars from six different countries were procured with 71 U.K. servicemen assessing two randomly allocated collars to rate one against the other. 58% of participants had worn UK neck collars previously on exercise, but only 6% had used them on operational tours. Body armor with shorter and thinner collars was rated the most comfortable, despite lying close to the neck. It was easier to aim a rifle wearing collars with overlapping segments, especially when in the prone position. Although higher and more rigid collars fared worse overall, this could potentially be offset by the higher levels of ballistic protection they provide. There is a need to evaluate other methods of protecting the neck such as nape protectors and ballistic scarves in combination with the use of backpacks and biometric data collection. Currently, there exists no agreed method of performing ergonomic (or human factor) assessments of the varying components of military body armor systems. Published standards for the minimum military performance requirements of the various components of body armor, including neck collars, need to be established.