Synthesis and degradation in vivo of a phosphoprotein from rat dental enamel. Identification of a phosphorylated precursor protein in the extracellular organic matrix.
The cellular enamel organ and the cell-free organic matrix of developing enamel of female rats injected intravascularly with [3H]serine and [3H]proline were extracted in a number of solvents and examined by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and h.p.l.c. in 6M-guanidinium chloride at intervals varying from 5 min to 1 week after injection. Three major species soluble in NH4HCO3 with Mr values of approx. 100 000, 25 000 and 11 000 were identified in the cellular enamel organ. The Mr 100 000 and 11 000 components were not secreted but remained intracellular for periods of up to 1 week after injection of the radioactively labelled amino acids. In contrast, the Mr 25 000 species was secreted from the cells and was first detected in the extracellular organic matrix approx. 15-30 min after injection. With time, labelled components, first of Mr approx. 11 000 and subsequently approx. 6500, were detected in the organic matrix concomitant with a relative decrease in the Mr 25 000 component, demonstrating that the lower Mr species were derived from degradation of the putative extracellular precursor protein (Mr 25 000). All of the extracellular components were found to contain O-phosphoserine. No radioactively labelled component with an Mr greater than approx. 25 000, either an amelogenin or an enamelin, was observed in the extracellular organic matrix or in an intracellular component which subsequently was lost from the intracellular pool. The Mr of the highest Mr protein or class of proteins is calculated to be approx. 22 000-26 000 when standard proteins are used as markers, but only 15 000-18 000 when using the CNBr peptides of alpha 1 chains of rat tail tendon collagen as markers.


[Structural reorganization in the lining epithelium of airways and respiratory areas of the lungs following exposure to hydrogen sulfide-containing gas mixture].
Structural reorganization of epithelium lining of pulmonary airways and respiratory portions was studied experimentally in outbred albino rats exposed to low doses (10 (g/m3) of hydrogen sulfide-containing gas mixture (natural gas + air) using the methods of histoautoradiography, electron microscopy and immunohistochemistry. Daily 1-hour-long exposure to gas mixture for up to 14 days resulted in moderate stimulating effect on specialized cells of bronchial epithelium. Following more protracted exposure to gas mixture (up to 1 month), the process demonstrated the involvement of protective mechanisms operating not only at the subcellular, but also at the tissue level, that was revealed by activation of DNA-synthesizing capacity of bronchial epithelial cells. Secretory Clara cells serving as the outpost of respiratory portion, were found to be significantly activated. The reversibility of the structural modifications in the pulmonary epithelia was demonstrated by the study of the organ 1 week following the discontinuation of a 1-month-long exposure to gas mixture.


Waning intestinal immunity after vaccination with oral poliovirus vaccines in India.
The eradication of wild-type polioviruses in areas with efficient fecal-oral transmission relies on intestinal mucosal immunity induced by oral poliovirus vaccine (OPV). Mucosal immunity is thought to wane over time but the rate of loss of protection has not been examined. We examined the degree and duration of intestinal mucosal immunity in India by measuring the prevalence of vaccine poliovirus in stool samples collected 4-28 days after a "challenge" dose of OPV among 47 574 children with acute flaccid paralysis reported during 2005-2009. Previous vaccination with OPV was protective against excretion of vaccine poliovirus after challenge, but the odds of excretion increased significantly with the time since the child was last exposed to an immunization activity (odds ratio, 1.39 [95% confidence interval .99-1.97], 2.04 [1.28-3.25], and 1.31 [1.00-1.70] comparing ≥6 months with 1 month ago for serotypes 1, 2, and 3, respectively). Vaccine administered during the high season for enterovirus infections (April-September) was significantly less likely to result in excretion, especially in northern states (odds ratio, 0.57 [95% confidence interval, .50-.65], 0.58 [.41-.81], and 0.48 [.40-.57] for serotypes 1, 2, and 3). Infection with OPV (vaccine "take") is highly seasonal in India and results in intestinal mucosal immunity that appears to wane significantly within a year of vaccination.


Towards a global framework for assessing male involvement in maternal health: results of an international Delphi study.
Currently, no standard instrument exists for assessing the concept of male involvement in maternal health, hampering comparison of results and interpretation of the literature. The aim of this study was to construct the key elements of a global multidimensional male involvement framework, based on the latest evidence and input of experts in the field. For this purpose, a Delphi study, including an international panel of 26 experts, was carried out. The study consisted of three rounds, with 92% of respondents completing all three surveys. Experts were asked to rate indicators within six categories in terms of validity, feasibility, sensitivity, specificity and context robustness. Furthermore, they were encouraged to clarify their rating with open text responses. Indicators were excluded or adapted according to experts' feedback before inclusion. A 85% agreement was used as threshold for consensus. A general consensus was reached for a global framework for assessing male involvement in maternal health, consisting of five categories: involvement in communication, involvement in decision-making, practical involvement, physical involvement and emotional involvement. Using the male involvement framework as a tool to assess the concept of male involvement in maternal health at local, national, and international levels could allow improved assessment and comparison of study findings. Further research is needed for refining the indicators according to context and exploring how shared decision-making, gender equality and women's empowerment can be assessed and facilitated within male involvement programmes.


Allocation, not male resistance, increases male frequency during epidemics: a case study in facultatively sexual hosts.
Why do natural populations vary in the frequency of sexual reproduction? Virulent parasites may help explain why sex is favored during disease epidemics. To illustrate, we show a higher frequency of males and sexually produced offspring in natural populations of a facultative parthenogenetic host during fungal epidemics. In a multi-year survey of 32 lakes, the frequency of males (an index of sex) was higher in populations of zooplankton hosts with larger epidemics. A lake mesocosm experiment established causality: experimental epidemics produced a higher frequency of males relative to disease-free controls. One common explanation for such a pattern involves Red Queen (RQ) dynamics. However, this particular system lacks key genetic specificity mechanisms required for the RQ, so we evaluated two other hypotheses. First, individual females, when stressed by infection, could increase production of male offspring vs. female offspring (a tenant of the "Abandon Ship" theory). Data from a life table experiment supports this mechanism. Second, higher male frequency during epidemics could reflect a purely demographic process (illustrated with a demographic model): males could resist infection more than females (via size-based differences in resistance and mortality). However, we found no support for this resistance mechanism. A size-based model of resistance, parameterized with data, revealed why: higher male susceptibility negated the lower exposure (a size-based advantage) of males. These results suggest that parasite-mediated increases in allocation to sex by individual females, rather than male resistance, increased the frequency of sex during larger disease epidemics.


Extreme long-term outcome of operatively versus conservatively treated patients with adolescent idiopathic scoliosis.
We report on outcomes of surgically versus (vs) non-surgically treated patients with moderate adolescent idiopathic scoliosis (AIS) after minimum of 29 years. AIS patients with a follow-up of ≥ 41 years in the surgical group and ≥ 29 years in the non-surgical group were included. Patients were treated surgically for primary curves ≥ 45° vs non-surgically for curves < 45° or refusal of surgery. Groups were matched for age, gender, comorbidities and primary curve severity. Oswestry Disability Index (ODI) was used to measure clinical outcomes and standard radiography to quantify curve severity at final follow-up. In total, 16 patients (8 within each group, 75% females) with a median age of 14 (interquartile range (IQR) 2) years could be included and were followed up after 46 (IQR 12) years. All matched variables were similar for both groups, including the primary curve Cobb angles of 48° (IQR 17°) (surgical) vs 40° (IQR 19°) (non-surgical); p = 0.17). At final follow-up after a median of 47 (IQR 5) years for the surgical and 39 (IQR 19) years for the non-surgical group (p = 0.43), the ODI was similar for both groups (15 (IQR 13) points (surgical) vs 7 (IQR 15) points (non-surgical); p = 0.17) with, however, a primary curve magnitude lower in the surgical compared to the non-surgical group (38° (IQR 3°) vs 61° (IQR 33°); p = 0.01), respectively. After around 47 and 39 years, respectively, surgical and non-surgical treatment of moderate AIS showed similar subjective outcomes, but with a relevant smaller curve magnitude with surgical treatment. III.


Performance evaluation of a conformal thermal monitoring sheet sensor array for measurement of surface temperature distributions during superficial hyperthermia treatments.
This paper presents a novel conformal thermal monitoring sheet (TMS) sensor array with differential thermal sensitivity for measuring temperature distributions over large surface areas. Performance of the sensor array is evaluated in terms of thermal accuracy, mechanical stability and conformity to contoured surfaces, probe self-heating under irradiation from microwave and ultrasound hyperthermia sources, and electromagnetic field perturbation. A prototype with 4 x 4 array of fiber-optic sensors embedded between two flexible and thermally conducting polyimide films was developed as an alternative to the standard 1-2 mm diameter plastic catheter-based probes used in clinical hyperthermia. Computed tomography images and bending tests were performed to evaluate the conformability and mechanical stability respectively. Irradiation and thermal barrier tests were conducted and thermal response of the prototype was compared with round cross-sectional clinical probes. Bending and conformity tests demonstrated higher flexibility, dimensional stability and close conformity to human torso. Minimal perturbation of microwave fields and low probe self-heating was observed when irradiated with 915 MHz microwave and 3.4 MHz ultrasound sources. The transient and steady state thermal responses of the TMS array were superior compared to the clinical probes. A conformal TMS sensor array with improved thermal sensitivity and dimensional stability was investigated for real-time skin temperature monitoring. This fixed-geometry, body-conforming array of thermal sensors allows fast and accurate characterization of two-dimensional temperature distributions over large surface areas. The prototype TMS demonstrates significant advantages over clinical probes for characterizing skin temperature distributions during hyperthermia treatments of superficial tissue disease.


The institutional design of forest certification standards initiatives and its influence on the role of science: the case of forest genetic resources.
In the 1990s a wide array of non-governmental certification initiatives emerged as a way to promote the sustainable management of resources in sectors such as fisheries and forestry. In this paper, we examine two related questions about these initiatives: how does the institutional design of certification initiatives affect the way science is used in the development of certification standards and in whose interest is science employed? Using the empirical case of forest certification and the specific standards various initiatives have created to address the management of forest genetic resources, we show how structural aspects of decision-making processes affects the standards adopted and the rationalization for their appropriateness. Two basic models of decision-making-stakeholder participation and technical expertise-are discussed in relation to three certification initiatives active in North America-the Canadian Standards Association, the Sustainable Forestry Initiative and the Forest Stewardship Council. By examining the standards these initiatives set for the management of forest genetic resources, we illustrate how two dimensions of science-uncertainty and the logic of cause and effect-are used to rationalize cautious and rigid versus flexible and discretionary standards for the management of forest genetic resources. Our findings indicate that the design or structure of certification decision-making processes, and their embedded balance of authority, mediate the form of standards initiatives will justify on the basis of science.


Sample Size Requirements for Structural Equation Models: An Evaluation of Power, Bias, and Solution Propriety.
Determining sample size requirements for structural equation modeling (SEM) is a challenge often faced by investigators, peer reviewers, and grant writers. Recent years have seen a large increase in SEMs in the behavioral science literature, but consideration of sample size requirements for applied SEMs often relies on outdated rules-of-thumb. This study used Monte Carlo data simulation techniques to evaluate sample size requirements for common applied SEMs. Across a series of simulations, we systematically varied key model properties, including number of indicators and factors, magnitude of factor loadings and path coefficients, and amount of missing data. We investigated how changes in these parameters affected sample size requirements with respect to statistical power, bias in the parameter estimates, and overall solution propriety. Results revealed a range of sample size requirements (i.e., from 30 to 460 cases), meaningful patterns of association between parameters and sample size, and highlight the limitations of commonly cited rules-of-thumb. The broad "lessons learned" for determining SEM sample size requirements are discussed.


Comparative analysis of olive oil organogels containing beeswax and sunflower wax with breakfast margarine.
The purpose of this research was to develop olive oil organogels with sunflower wax (SW) and beeswax (BW) at 3%, 7%, and 10% addition levels and to compare these organogels with breakfast margarine (BM). The organogels and BM sample were stored at 2 different temperatures (4 and 20 °C), and the peroxide values (PVs) and textural properties were monitored for 3 mo. The PVs of all organogels were within legal limits and the gels were structurally stable throughout the storage period. The textural properties of 3% SW and 7% BW organogels were closely similar to BM. The solid fat contents of the organogels were lower than that of the BM. Moreover, the thermal properties of 3% BW gel were more similar to that of the BM. The results of X-ray diffraction peaks, approximately 3.70 and 4.10 Å, were similar to β' polymorphic form. In conclusion, both of the organogel types may have value in replacing BMs.


Diabetic complications in a patient with coexisting anterior hypopituitarism.
We present a patient who developed insulin-requiring diabetes several years after the onset of symptoms of anterior hypopituitarism. It is likely that the hypopituitarism protected him against the development of diabetic retinopathy and glomerular basement membrane thickening but not against neuropathy and atheroma. The significance of this in relation to the growth-hormone-microangiopathy hypothesis is discussed.


Ketamine and xylazine for surgical anesthesia in rats.
The responses of 2 inbred strains of rats to intramuscular doses of ketamine and xylazine, singly and in combination, were studied. A synergistic effect was observed when the 2 drugs were administered together, which resulted in anesthesia with extended analgesia and immobility. Anesthesia was achieved in most rats given 87 mg ketamine/kg of body weight and 13 mg xylazine/kg, beginning 10 to 15 minutes after simultaneous injection and lasting 15 to 30 minutes, then followed by a relatively long period of immobility (mean, 3.8 hours) and reduced responsiveness to external stimuli. Some rats required up to twice this dose for adequate surgical anesthesia. Total doses (initial and supplemental) of up to 3 times the amount were administered with apparent safety.


The effect of various immunosuppressive agents on mouse peritoneal macrophages and on the in vitro phagocytosis of Escherichia coli O4:K3:H5 and degradation of 125I-labelled HSA-antibody complexes by these cells.
Large doses of hydrocortisone, cyclophosphamide, and methotrexate injected subcutaneously, and whole-body irradiation (500 rads) caused a reduction in the number of peritoneal cells (PE cells) obtained after intraperitoneal injection of the treated mice with proteose-peptone. The same dose of cyclophosphamide and irradiation induced morphological changes in PE macrophages. There were more giant cells in the peritoneal exudates from treated mice as compared to control mice. 'Pharmacological' and larger doses of hydrocortisone, methotrexate and azathioprine or anti-lymphocyte globulin had no effect on the in vitro phagocytic capacity of proteose-peptone-stimulated mouse PE macrophages. This also applied to doses of up to 50 mg/kg of cyclophosphamide. In contrast, whole-body irradiation (500 rad) and 100 mg/kg of cyclophosphamide decreased the phagocytic capacity of mouse macrophages in vitro and reduced the ability of PE cells to degrade 125I-labelled HSA-antibody complexes in vitro. The greatest effect was noted 4-5 days after whole-body irradiation or four to five subcutaneous injections of cyclophosphamide.


[Clinical analysis of 14 cases with childhood acute lymphoblastic leukemia complicated with tropical candidemia].
Objective: To investigate the clinical feature, diagnosis, treatment and prognosis of childhood acute lymphoblastic leukemia (ALL) complicated with candida tropicalis bloodstream infection (CTBI), so as to improve the understanding of this disease. Methods: The general information, clinical manifestation, auxiliary examination, treatment and outcome of 14 childhood ALL who were diagnosed with tropical candidemia between January 2015 and December 2018 in 6 hospitals were analyzed retrospectively. Clinical data of non invasive fungal disease (IFD) ALL (28 cases) and other IFD children (9 cases) admitted in the same period were collected as control group. Logistic regression model was used to analyze the risk factor of CTBI. Results: Among 14 cases, there were 7 males and 7 females, with the age ranged from 17 months to 13 years. All the cases had fever, 9 cases had digestive system symptoms and stool fungal culture were positive in 3 of them; 7 cases had respiratory system symptoms and sputum fungal culture was positive in 1 of them; 2 cases had central nervous system symptoms and 10 cases progressed into septic shock. All 14 cases had neutropenia and the neutropenia duration was 1 to 53 days. Among 14 cases, the C-reactive protein was>50 mg/L in 8 cases, in which the proportion was significantly higher than that in other invasive fungal disease(IFD) (8/14 vs. 1/9, P<0.05), meanwhile the 1, 3-β-D-glucan detection, galactomannan detection and pulmonary imaging were not remarkable in all 14 cases. The blood culture results of 14 cases were all candida tropicalis, among which 13 cases finished drug susceptibility tests, the isolates of all cases were sensitive to flucytosine and amphotericin B, and the isolates of 4 cases were sensitive to fluconazole, voriconazole and itraconazole. Among 14 cases, 1 case lost to follow-up after giving up treatment, 1 case died before antifungal therapy and the remaining 12 cases received antifungal therapy; 7 of the 14 cases died. Univariate analysis showed that between ALL with CTBI group (14 cases) and ALL without invasive fungal disease (IFD) group (28 cases), the differences in variables such as ALL not in remission (χ²=37.847, P<0.01), length of hospital stay>15 days (χ2=8.351, P=0.004), neutropenia (χ²=14.280, P<0.01), neutropenia duration>10 days (χ²=10.254, P=0.001), use of broad-spectrum antibiotics (χ²=13.888, P<0.01), skin and mucous membrane damage (χ²= 5.923, P=0.015) were statistically significant. Conclusions: In childhood ALL complicated with tropical candidemia, the drug resistance rate and mortality rate were high. For azole-resistant tropical candida, amphotericin B liposome or echinocandins(caspofungin) -fluorocytosine combined therapy was recommended to reduce treatment-related deaths.


Utilisation of strategic communication to create willingness to change work practices among primary care staff: a long-term follow-up study.
To evaluate the long-term utilisation of strategic communication as a factor of importance when changing work practices among primary care staff. In many health care organisations, there is a gap between theory and practice. This gap hinders the provision of optimal evidence-based practice and, in the long term, is unfavourable for patient care. One way of overcoming this barrier is systematically structured communication between the scientific theoretical platform and clinical practice. This longitudinal evaluative study was conducted among a primary care staff cohort. Strategic communication was considered to be the intervention platform and included a network of ambassadors who acted as a component of the implementation. Measurements occurred 7 and 12 years after formation of the cohort. A questionnaire was used to obtain information from participants. In total, 846 employees (70%) agreed to take part in the study. After 12 years, the 352 individuals (60%) who had remained in the organisation were identified and followed up. Descriptive statistics and multivariate analysis were used to analyse the data. Continuous information contributed to significant improvements over time with respect to new ideas and the intention to change work practices. There was a statistically significant synergistic effect on the new way of thinking, that is, willingness to change work practices. During the final two years, the network of ambassadors had created a distinctive image for itself in the sense that primary care staff members were aware of it and its activities. This awareness was associated with a positive change with regard to new ways of thinking. More years of practice was inversely associated with willingness to change work practices. Strategic communication may lead to a scientific platform that promotes high-quality patient care by means of new methods and research findings.


Impact of individual and worksite environmental factors on water and sugar-sweetened beverage consumption among overweight employees.
The worksite environment may influence employees' dietary behaviors. Consumption of water and sugar-sweetened beverages (SSBs) affect weight management; however, little research has evaluated the influence of worksite factors on beverage consumption. Our purpose was to determine whether individual and worksite factors are associated with water and SSB intake among overweight and obese employees. Data were collected as part of baseline assessments for a worksite-based, weight-management intervention trial. Height and weight of participants (N = 1,482; 74% female; mean age = 47 y [standard deviation (SD) = 11 y]; mean weight = 208 lbs [SD = 46 lbs]) were assessed, and participants completed a validated beverage intake questionnaire. Environmental characteristics of worksites (N = 28) were audited. A qualitative comparative analysis (QCA) was used to identify worksite conditions that may support healthier beverage intake patterns. Most participants were white (75% of sample) with at least some college education or a college degree (approximately 82% of sample). Mean water and SSB intake were 27 fl oz (SD = 18 fl oz) and 17 fl oz (SD = 18 fl oz), respectively; SSB intake (191 kcal [SD = 218 kcal]) exceeded the recommended discretionary energy intake. Statistical models did not identify any significant predictors of water intake. Female sex and increasing level of education and household income were associated with lower SSB intake; baseline body weight and greater number of worksite water coolers and vending machines were associated with higher SSB intake. The QCA identified worksite type (ie, not manual labor) as a condition necessary for healthier beverage consumption; a worksite break policy of 2 or more per day may lead to unhealthy beverage consumption. Lower SSB consumption was noted among older participants, female participants, and among participants with higher education and income levels. Workplace factors influence beverage consumption among overweight employees. Limiting vending machine availability and implementing policies that promote weight management may improve employee health.


Systematic review of the role of high intensity focused ultrasound (HIFU) in treating malignant lesions of the hepatobiliary system.
High Intensity Focused Ultrasound (HIFU) is an emerging non-invasive, targeted treatment of malignancy. The aim of this review was to assess the efficacy, safety and optimal technical parameters of HIFU to treat malignant lesions of the hepatobiliary system. A systematic search of the English literature was performed until March 2020, interrogating Pubmed, Embase and Cochrane Library databases. The following key-words were input in various combinations: 'HIFU', 'High intensity focussed ultrasound', 'Hepatobiliary', 'Liver', 'Cancer' and 'Carcinoma'. Extracted content included: Application type, Exposure parameters, Patient demographics, and Treatment outcomes. Twenty-four articles reported on the clinical use of HIFU in 940 individuals to treat malignant liver lesions. Twenty-one studies detailed the use of HIFU to treat hepatocellular carcinoma only. Mean tumour size was 5.1 cm. Across all studies, HIFU resulted in complete tumour ablation in 55% of patients. Data on technical parameters and the procedural structure was very heterogeneous. Ten studies (n = 537 (57%) patients) described the use of HIFU alongside other modalities including TACE, RFA and PEI; 66% of which resulted in complete tumour ablation. Most common complications were skin burns (15%), local pain (5%) and fever (2%). HIFU has demonstrated benefit as a treatment modality for malignant lesions of the hepatobiliary system. Combining HIFU with other ablative therapies, particularly TACE, increases the efficacy without increasing complications. Future human clinical studies are required to determine the optimal treatment parameters, better define outcomes and explore the risks and benefits of combination therapies.


Once-a-week or every-other-day urethra-sparing prostate cancer stereotactic body radiotherapy, a randomized phase II trial: 18 months follow-up results.
To present the 18 months results from a prospective multicenter phase II randomized trial of short vs protracted urethra-sparing stereotactic body radiotherapy (SBRT) for localized prostate cancer (PCa). Between 2012 and 2015, a total of 170 PCa patients were randomized to 36.25 Gy in 5 fractions (6.5 Gy × 5 to the urethra) delivered either every other day (EOD, arm A, n = 84) or once a week (QW, arm B, n = 86). Genitourinary (GU) and gastrointestinal (GI) toxicity (CTCAE v4.0 scale), IPSS, and QoL scores were assessed at baseline, at the 5th fraction (5fx), 12th weeks (12W), and every 6 months after SBRT. The primary endpoint was biochemical control at 18 months and grade ≥ 3 toxicity (including grade ≥ 2 for urinary obstruction/retention) during the first 3 months. Among the 165 patients analyzed, the toxicity stopping rule was never activated during the acute phase. Maximum acute grade 2 GU toxicity rates at 5fx were 17% and 19% for arms A and B, respectively, with only 2 cases of grade 2 GI toxicity at 5fx in arm A. At month 18, grade ≥ 2 GU and GI toxicity decreased below 5% and 2% for both arms. No changes in EORTC QLQ-PR25 scores for GU, GI, and sexual domains were observed in both arms between baseline and month 18. Four biochemical failures were observed, 2 in each arm, rejecting the null hypothesis of an unfavorable response rate ≤ 85% in favor of an acceptable ≥ 95% rate. At 18 months, urethra-sparing SBRT showed a low toxicity profile, with minimal impact on QoL and favorable biochemical control rates, regardless of overall treatment time (EOD vs QW).


Brr2 plays a role in spliceosomal activation in addition to U4/U6 unwinding.
Brr2 is a DExD/H-box RNA helicase that is responsible for U4/U6 unwinding, a critical step in spliceosomal activation. Brr2 is a large protein (∼250 kD) that consists of an N-terminal domain (∼500 residues) with unknown function and two Hel308-like modules that are responsible for RNA unwinding. Here we demonstrate that removal of the entire N-terminal domain is lethal to Saccharomyces cerevisiae and deletion of the N-terminal 120 residues leads to splicing defects and severely impaired growth. This N-terminal truncation does not significantly affect Brr2's helicase activity. Brr2-Δ120 can be successfully assembled into the tri-snRNP (albeit at a lower level than the WT Brr2) and the spliceosomal B complex. However, the truncation significantly impairs spliceosomal activation, leading to a dramatic reduction of U5, U6 snRNAs and accumulation of U1 snRNA in the B(act) complex. The N-terminal domain of Brr2 does not seem to be directly involved in regulating U1/5'ss unwinding. Instead, the N-terminal domain seems to be critical for retaining U5 and U6 snRNPs during/after spliceosomal activation through its interaction with snRNAs and possibly other spliceosomal proteins, revealing a new role of Brr2 in spliceosomal activation in addition to U4/U6 unwinding.


Assessing the Influence of Environmental Sources on the Gut Mycobiome of Tibetan Macaques.
The distribution and availability of microbes in the environment has an important effect on the composition of the gut microbiome of wild vertebrates. However, our current knowledge of gut-environmental interactions is based principally on data from the host bacterial microbiome, rather than on links that establish how and where hosts acquire their gut mycobiome. This complex interaction needs to be clarified. Here, we explored the relationship between the gut fungal communities of Tibetan macaques (Macaca thibetana) and the presence of environmental (plant and soil) fungi at two study sites using the fungal internal transcribed spacer (ITS) and next generation sequencing. Our findings demonstrate that the gut, plant and soil fungal communities in their natural habitat were distinct. We found that at both study sites, the core abundant taxa and ASVs (Amplicon Sequence Variants) of Tibetan macaques' gut mycobiome were present in environmental samples (plant, soil or both). However, the majority of these fungi were characterized by a relatively low abundance in the environment. This pattern implies that the ecology of the gut may select for diverse but rare environmental fungi. Moreover, our data indicates that the gut mycobiome of Tibetan macaques was more similar to the mycobiome of their plant diet than that present in the soil. For example, we found three abundant ASVs (Didymella rosea, Cercospora, and Cladosporium) that were present in the gut and on plants, but not in the soil. Our results highlight a relationship between the gut mycobiome of wild primates and environmental fungi, with plants diets possibly contributing more to seeding the macaque's gut mycobiome than soil fungi.


The clinical characteristics of steroid responsive nephrotic syndrome of children according to the serum immunoglobulin E levels and cytokines.
The nephrotic syndrome (NS) is characterized by the favorable response to glucocorticoid therapy and the development of NS may be associated with dysfunctional immune systems. In order to investigate the serum immunoglobulin E (IgE) levels and cytokines activity in pediatric NS, the total of 32 steroid responsive NS patients and 5 healthy controls were enrolled in this study. All patients were divided into two groups according to the initial serum IgE levels, such as normal and high IgE group, and their clinical characteristics were evaluated. In addition, serum levels of interleukin (IL)-4, IL-5, IL-10 and transforming growth factor (TGF)-β were compared and correlated with serum albumin, proteinuria by means of disease severity, and cytokines. In the high IgE group, the higher comorbidity of allergic diseases and relapsing rate, the longer duration of steroid therapy before initial remission, and the higher serum IL-4 and IL-5 levels were found. In all patients, initially higher serum levels of IL-4 and IL-5 declined to normal levels after steroid therapy, whereas the serum IL-10 levels showed no significant difference between nephrotic phase (heavy proteinuria) and remission phase (no proteinuria) of NS. The serum TGF-β levels of the nephrotic phase were significantly lower than those of remission phase or control group, and returned to normal control levels after steroid therapy. This study indicates that initial IgE level is associated with steroid responsiveness and disease severity, and cytokine activities may also be related to the pathogenesis of pediatric steroid responsive NS.


Confronting Compassion Fatigue: Assessment and Intervention in Inpatient Oncology .
A notable variation among patient satisfaction scores with nursing care was identified. Contributing factors were examined and revealed significant negative correlations between the unit death rate and surviving patients' satisfaction scores. Compassion fatigue (CF) was hypothesized to be a major contributing factor. . The objective was to address CF in RNs and oncology care associates (assistive personnel) by developing an intervention to provide bereavement support to staff after patient deaths. . A mixed-methods sequential design was used. Instruments included the Professional Quality of Life scale and Press Ganey survey results. Univariate descriptive statistics, frequencies, an independent t test, and an analysis of covariance were used for data analysis. . The preintervention results revealed average compassion satisfaction and secondary traumatic stress scores and low burnout scores. No significant difference was noted between pre- and postintervention CF scores. Patients' perception of nurses' skills improved significantly in the second quarter of 2015.


From local to global-fifty years of research on Salvia divinorum.
In 1962 ethnopharmacologists, Hofmann and Wasson, undertook an expedition to Oaxaca, Mexico. These two researchers were the first scientists to collect a flowering specimen of Salvia divinorum allowing the identification of this species. While the species' traditional use is confined to a very small region of Mexico, since Hofmann and Wasson's expedition 50 years ago, Salvia divinorum has become globally recognized for its main active constituent, the diterpene salvinorin A, which has a unique effect on human physiology. Salvinorin A is a kappa-opioid agonist and the first reported psychoactive diterpene. This review concentrates on the investigation of Salvia divinorum over the last 50 years including ethnobotany, ethnopharmacology, taxonomy, systematics, genetics, chemistry and pharmacodynamic and pharmacokinetic research. For the purpose of this review, online search engines were used to find relevant research. Searches were conducted between October 2011 and September 2013 using the search term "Salvia divinorum". Papers were excluded if they described synthetic chemical synthesis of salvinorin A or analogues. Ethnobotanically there is a comprehensive body of research describing the traditional Mazatec use of the plant, however, the modern ethnobotanical use of this plant is not well documented. There are a limited number of botanical investigations into this plant and there are still several aspects of the botany of Salvia divinorum which need further investigation. One study has investigated the phylogenetic relationship of Salvia divinorum to other species in the genus. To date the main focus of chemistry research on Salvia divinorum has been salvinorin A, the main active compound in Salvia divinorum, and other related diterpenoids. Finally, the effects of salvinorin A, a KOR agonist, have primarily been investigated using animal models. As Salvia divinorum use increases worldwide, the emerging cultural use patterns will warrant more research. More botanical information is also needed to better understand this species, including germination, pollination vector and a better understanding of the endemic environment of Salvia divinorum. As well there is a gap in the genetic knowledge of this species and very little is known about its intra-species genetics. The terpenes in Salvia divinorum are very well documented, however, other classes of constituents in this species warrant further investigation and identification. To date, the majority of the pharmacology research on Salvia divinorum has focused on the effects of salvinorin A using animal models. Published human studies have not reported any harmful effects when salvinorin A is administered within the dose range of 0.375-21µg/kg but what are the implications when applied to a larger population? More data on the toxicology and safety of Salvia divinorum are needed before larger scale clinical trials of the potential therapeutic effects of Salvia divinorum and salvinorin A are undertaken.


Parvovirus B19-induced thrombocytopenia and anemia in a child with fatal fulminant hepatic failure coinfected with hepatitis A and E viruses.
A 5-year-old male, drowsy, jaundiced child presented with fulminant hepatitis and had HAV and HEV infection. He had hepatic encephalopathy grade 1, fever, pallor, hypotension, crepitations in his right lung base and hepatosplenomegaly with dyspnoea. He had highly raised liver enzymes and hypoalbuminemia (2.8 g/dl) but anemia (hemoglobin of 7.7 g/dl and 5.7 g/dl 2 days later), reticulocytopenia and severe thrombocytopenia (44 x 10(9)/l) were unexplained. Parvovirus B19-specific IgM antibodies and B19 DNA were found in the serum of the child. Chest X-ray showed pleural effusion and bronchopneumonia, while blood culture isolated coagulase-negative staphylococci (BACTEC 9120) and he had low oxygen saturation. Hence, he was treated with IV amoxicillin+ clavulinic acid and oxygen inhalation. He had seizures and cardiac arrest but was revived. On the third day his condition worsened and the child died despite intensive care. Hence it is concluded that his anemia and thrombocytopenia were B19 induced and this might have aggravated or caused fulminant hepatitis.


CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation.
The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.


Treatment recommendations for chronic myeloid leukemia.
The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.


School factors related to the emotional wellbeing and resettlement outcomes of students from refugee backgrounds: protocol for a systematic review.
Schools can play a vital role in the resettlement of refugee children and their families. Yet, the body of research examining school environmental factors that support the mental health and acculturation of refugee children is methodologically heterogeneous, investigates numerous and disparate school factors, and is often "hidden" in broader qualitative studies. This limits the capacity to apply the findings in a practical manner. Based on PRISMA statement principles, we review the relevant literature to investigate the relationship between school climate and the emotional wellbeing and resettlement outcomes of refugee students. Six electronic databases will be systematically searched: MEDLINE, PsycINFO, Embase, CINAL, Web of Science, and ERIC, supplemented by a systematic review of the grey literature, relevant international websites, and sequential, site-specific internet searches. Finally, subject area experts will be consulted and backward and forward citation searches of included articles will be completed. Two independent reviewers will screen identified articles against eligibility criteria and extract data for included studies. Quality of included studies will be assessed using the Mixed Methods Appraisal Tool (MMAT) for mixed studies reviews. Data will be synthesised using a convergent qualitative narrative approach. Given the centrality of school in the daily lives of resettled refugee children, it is vital to assess the impact of school climate on the psychosocial wellbeing and resettlement trajectories of this population. This review will identify evidence-based school factors which support good mental health and resettlement outcomes for refugee students and make recommendations for translation of this knowledge into the school environment. PROSPERO CRD42017077570.


Jones matrix for image-rotation prisms.
The polarization-transforming properties of rotational prisms are analyzed with polarized light by using the Jones calculus and the exact ray-trace. A general expression of the Jones matrix for a rotational prism is derived, incorporating an explicit dependence on the image-rotation angle or the wave-front-rotation angle. The Jones matrix for the Pechan, Dove, Reversion, and Delta prisms is derived where the explicit dependence on the angle of rotation of the image is given. An experiment with a rotating Dove prism is also conducted to determine the output states of polarization for incident linearly polarized light. Experimental results agree with theoretical expectations.


Interaction of soluble glucosyl- and mannosyl-transferase enzyme activities in the synthesis of a glucomannan.
A neutral-detergent-solubilized-enzyme preparation derived from Phaseolus aureus hypocotyls contains two types of glycosyltransferase activity. One, mannosyltransferase enzyme activity, utilizes GDP-alpha-d-mannose as the sugar nucleotide substrate. The other, glucosyltransferase enzyme activity, utilizes GDP-alpha-d-glucose as the sugar nucleotide substrate. The soluble enzyme preparation catalyses the formation of what appears to be a homopolysaccharide when either sugar nucleotide is the only substrate present. A beta-(1-->4)-linked mannan is the only polymeric product when only GDP-alpha-d-mannose is added. A beta-(1-->4)-linked glucan is the only polymeric product when only GDP-alpha-d-glucose is added. In the presence of both sugar nucleotides, however, a beta-(1-->4)-linked glucomannan is formed. There are indications that endogenous sugar donors may be present in the enzyme preparation. There appear to be only two glycosyltransferases in the enzyme preparation, each catalysing the transfer of a different sugar to the same type of acceptor molecule. The glucosyltransferase requires the continual production of mannose-containing acceptor molecules for maintenance of enzyme activity, and is thereby dependent upon the activity of the mannosyltransferase. The mannosyltransferase, on the other hand, does not require the continual production of glucose-containing acceptors for maintenance of enzyme activity, but is severely inhibited by GDP-alpha-P-glucose. These properties promote the synthesis of beta-(1-->4)-linked glucomannan rather than beta-(1-->4)-linked glucan plus beta-(1-->4)-linked mannan when both sugar nucleotide substrates are present.


Baculovirus-expressed glycoprotein H of herpes simplex virus type 1 (HSV-1) induces neutralizing antibody and delayed type hypersensitivity responses, but does not protect immunized mice against lethal HSV-1 challenge.
We have shown previously that herpes simplex virus type 1 (HSV-1) glycoprotein H (gH) expressed by a baculovirus recombinant is transported to the cell surface in the absence of other HSV-1 gene products, and that the expressed gH has an apparent Mr similar to that of authentic HSV-1 gH. We report here that antibodies raised in mice to this baculovirus-expressed gH neutralize the infectivity of HSV-1 in vitro; this neutralizing activity was not complement-dependent. Mice vaccinated with gH also developed delayed type hypersensitivity (DTH) to HSV-1. This is the first report of expressed HSV-1 gH inducing neutralizing antibody or DTH responses in vaccinated animals. In contrast to the gH expressed in mammalian systems, the ability of this baculovirus-expressed gH to induce a neutralizing antibody response may be due to the inability of the mammalian expression system to transport gH to the cell surface. Despite inducing anti-HSV-1 neutralizing antibody and DTH responses, vaccination of mice with gH did not protect the mice against lethal intraperitoneal challenge with HSV-1.


Shiga toxin-producing Escherichia coli O26:H11 associated with a cluster of haemolytic uraemic syndrome cases in South Africa, 2017.
Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens that may cause diarrhoeal outbreaks and occasionally are associated with haemolytic-uraemic syndrome (HUS). We report on STEC O26:H11 associated with a cluster of four HUS cases in South Africa in 2017. All case-patients were female and aged 5 years and under. Standard microbiological tests were performed for culture and identification of STEC from specimens (human stool and food samples). Further analysis of genomic DNA extracted from bacterial cultures and specimens included PCR for specific virulence genes, whole-genome sequencing and shotgun metagenomic sequencing. For 2/4 cases, stool specimens revealed STEC O26:H11 containing eae, stx2a and stx2b virulence genes. All food samples were found to be negative for STEC. No epidemiological links could be established between the HUS cases. Dried meat products were the leading food item suspected to be the vehicle of transmission for these cases, as 3/4 case-patients reported they had eaten this. However, testing of dried meat products could not confirm this. Since STEC infection does not always lead to severe symptoms, it is possible that many more cases were associated with this cluster and largely went unrecognized.


3d4f heterobimetallic dinuclear and tetranuclear complexes involving tetrathiafulvalene as ligands: X-ray structures and magnetic and photophysical investigations.
Six new 3d4f heterobimetallic dinuclear complexes, [(L(1))MLn(hfac)(3)] [M = Cu(II), Ni(II); Ln = Y(III), Er(III), Yb(III); L(1) = 4,5-bis(propylthio)tetrathiafulvalene-N,N'-phenylenebis(salicylideneimine) and hfac(-) = 1,1,1,5,5,5-hexafluoroacetylacetonate], and one tetranuclear complex, [(L(2))Cu(OH)Er(hfac)(3)](2) (where L(2) = 4,5-bis(propylthio)tetrathiafulvalene-N,N'-phenyleneaminosalicylideneimine), have been synthesized. All of the X-ray structures of the coordination complexes have been resolved from single-crystal diffraction. A quantitative magnetic approach has allowed one to determine the Cu-Ln ferromagnetic interaction for Gd(III) (1.29 cm(-1)) and Tb(III) (0.40 cm(-1)) and the antiferromagnetic interaction for Dy(III) (-0.46 cm(-1)) and Yb(III) (-2.25 cm(-1)), while in the case of Er(III), the magnetic interactions are negligible. The UV-visible absorption properties have been studied in a chloroform solution and rationalized by DFT and TD-DFT calculations. Upon oxidation, intramolecular SOMO → LUMO (20,800 cm(-1)) and SOMO-n → SOMO (11,350 cm(-1)) charge transfers appear, while the HOMO → LUMO charge transfers (20,750 cm(-1)) disappear. The reversibility of the oxidation has been confirmed by electrochemistry and absorption properties upon the addition of a reducing agent. Irradiation at the HOMO → LUMO charge-transfer energy of the dinuclear complex [(L(1))NiY(hfac)(3)] induces a ligand-centered fluorescence at 14,450 cm(-1).


Quercetin-3-methyl ether inhibits lapatinib-sensitive and -resistant breast cancer cell growth by inducing G(2)/M arrest and apoptosis.
Lapatinib, an oral, small-molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity. Here, we found that quercetin-3-methyl ether caused a significant growth inhibition of lapatinib-sensitive and -resistant breast cancer cells. Western blot data showed that quercetin-3-methyl ether had no effect on Akt or ERKs signaling in resistant cells. However, quercetin-3-methyl ether caused a pronounced G(2)/M block mainly through the Chk1-Cdc25c-cyclin B1/Cdk1 pathway in lapatinib-sensitive and -resistant cells. In contrast, lapatinib produced an accumulation of cells in the G(1) phase mediated through cyclin D1, but only in lapatinib-sensitive cells. Moreover, quercetin-3-methyl ether induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7, and poly(ADP-ribose) polymerase (PARP) in both cell lines. Overall, these results suggested that quercetin-3-methyl ether might be a novel and promising therapeutic agent in lapatinib-sensitive or -resistant breast cancer patients.


Effects of grain sorghum planting density and processing method on nutrient digestibility and retention by ruminants.
Grain sorghum grown in 38-cm rows (high density [HD]) or 76-cm rows (normal density [ND]) was treated as follows: steam-flaked (SF), high-moisture-harvested followed by rolling and ensiling (HM), or dry-rolled (DR). Resulting grains were evaluated using lambs in two 5 x 5 Latin square digestion trials. Treatment diets contained either SF-HD, SF-ND, HM-HD, HM-ND, or DR-ND grain sorghum in two trials; a 90 or a 60% concentrate diet was fed in each trial. High-density planting increased (P < 0.10) the apparent absorption of P relative to ND planting for both 60 and 90% concentrate diets. Steam flaking decreased (P < 0.10) the apparent absorption of P in the 90% concentrate diet and decreased (P < 0.10) the apparent absorption of N in both the 90 and 60% concentrate diets. Despite differences in N digestibility, steam flaking and HM ensiling resulted in similar (P > 0.10) N retention as a percentage of N intake in both trials. However, changes in the distribution of N between feces and urine among processing methods could affect N content of manure and alter nutrient management strategies. These results indicate that both planting density and grain processing can alter the apparent absorption of grain sorghum P by ruminants. Furthermore, it seems that grain processing can alter the route of N excretion in ruminants without changing total N retention.


Mitochondria and the future of RASopathies: the emergence of bioenergetics.
RASopathies are a family of rare autosomal dominant disorders that affect the canonical Ras/MAPK signaling pathway and manifest as neurodevelopmental systemic syndromes, including Costello syndrome (CS). In this issue of the JCI, Dard et al. describe the molecular determinants of CS using a myriad of genetically modified models, including mice expressing HRAS p.G12S, patient-derived skin fibroblasts, hiPSC-derived human cardiomyocytes, an HRAS p.G12V zebrafish model, and human lentivirally induced fibroblasts overexpressing HRAS p.G12S or HRAS p.G12A. Mitochondrial proteostasis and oxidative phosphorylation were altered in CS, and inhibition of the AMPK signaling pathway mediated bioenergetic changes. Importantly, the pharmacological induction of this pathway restored cardiac function and reduced the developmental defects associated with CS. These findings identify a role for altered bioenergetics and provide insights into more effective treatment strategies for patients with RASopathies.


Stokes space modulation format classification based on non-iterative clustering algorithm for coherent optical receivers.
A Stokes-space modulation format classification (MFC) technique is proposed for coherent optical receivers by using a non-iterative clustering algorithm. In the clustering algorithm, two simple parameters are calculated to help find the density peaks of the data points in Stokes space and no iteration is required. Correct MFC can be realized in numerical simulations among PM-QPSK, PM-8QAM, PM-16QAM, PM-32QAM and PM-64QAM signals within practical optical signal-to-noise ratio (OSNR) ranges. The performance of the proposed MFC algorithm is also compared with those of other schemes based on clustering algorithms. The simulation results show that good classification performance can be achieved using the proposed MFC scheme with moderate time complexity. Proof-of-concept experiments are finally implemented to demonstrate MFC among PM-QPSK/16QAM/64QAM signals, which confirm the feasibility of our proposed MFC scheme.


Post-exposure prophylaxis (PEP) for rabies with purified chick embryo cell vaccine: a systematic literature review and meta-analysis.
Fifteen million people each year receive post-exposure prophylaxis (PEP) to prevent rabies, yet the disease remains neglected and highly under-reported. In this systematic literature review, we assessed the immunogenicity, efficacy, and safety of a purified chick embryo cell-culture rabies vaccine (PCECV) for PEP against rabies by intramuscular (IM) or intradermal (ID) administration. We performed meta-analyses to compare immunogenicity according to the route of vaccine administration, study population, and PEP regimen, such as number of doses, and concomitant rabies immunoglobulin. There were 54 estimates of immune responses to vaccination, which showed that in the overall population, after starting PEP with PCECV by the IM or ID route (≥2.5 IU per dose), almost all individuals had rabies virus neutralizing antibody (RVNA) titers above the World Health Organization (WHO) recommended serological threshold for an adequate immune response to vaccination (RVNA ≥0.5 IU/ml by day 14). In the overall population, PCECV had an acceptable safety profile. However, given that there are 59,000 human rabies deaths reported annually, the challenge is to improve access to PCECV for PEP against human rabies.


Potentially Inappropriate Prescribing Among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database.
Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD). To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender. A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013-31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender. The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2- 65.5; n = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2-26.2; n = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6-8.7) and 1.3 (95% CI 1.2-1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy. This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy.


Case report: prosthodontic treatment for the transmandibular implant.
The Transmandibular Implant is a transosteal implant developed to help improve masticatory function in patients with severe mandibular atrophy. It is a functional implant with a rigid box frame design which allows acceptance of masticatory loads in mandibles with minimal bone height. The implant is fabricated of a gold alloy and is placed between the mental foramina from a submental approach. The prosthesis is fabricated as an overdenture and retention is obtained by means of retention sleeves adapted to Dolder bar segments of the superstructure. Denture comfort and function can be greatly improved for patients with severely resorbed mandibles.


Compications in acoustic neuroma surgery.
The findings in a series of 80 cerebellopontine angle tumors are presented. Complications and results are covered in detail. A new method of controlling postoperative cerebrospinal fluid (CSF) leak is presented. Care of the eye in postoperative facial paralysis is emphasized, and a new type of moisture chamber is introduced.


Structural brain abnormalities in 12 persons with aniridia.
Background: Aniridia is a disorder predominately caused by heterozygous loss-of-function mutations of the PAX6 gene, which is a transcriptional regulator necessary for normal eye and brain development. The ocular abnormalities of aniridia have been well characterized, but mounting evidence has implicated brain-related phenotypes as a prominent feature of this disorder as well. Investigations using neuroimaging in aniridia patients have shown reductions in discrete brain structures and changes in global grey and white matter. However, limited sample sizes and substantive heterogeneity of structural phenotypes in the brain remain a challenge. Methods: Here, we examined brain structure in a new population sample in an effort to add to the collective understanding of anatomical abnormalities in aniridia. The current study used 3T magnetic resonance imaging to acquire high-resolution structural data in 12 persons with aniridia and 12 healthy demographically matched comparison subjects. Results: We examined five major structures: the anterior commissure, the posterior commissure, the pineal gland, the corpus callosum, and the optic chiasm. The most consistent reductions were found in the anterior commissure and the pineal gland; however, abnormalities in all of the other structures examined were present in at least one individual. Conclusions: Our results indicate that the anatomical abnormalities in aniridia are variable and largely individual-specific. These findings suggest that future studies investigate this heterogeneity further, and that normal population variation should be considered when evaluating structural abnormalities.


A novel piperazine derivative potently induces caspase-dependent apoptosis of cancer cells via inhibition of multiple cancer signaling pathways.
Despite rapid progress in anticancer drug development and improvement in clinical outcomes, the survival rate for many types of cancer is still unacceptably low. Therefore, it is crucial to discover novel anticancer drugs to both prevent and treat the disease. In recent years, the advent of combinatorial chemistry allows the design and parallel synthesis of millions of small compounds that have drug-like properties. In vitro high throughput screening of such compound libraries has allowed the identification of many new drug candidates that may be further evaluated for their efficacy and mechanism of action. The overall objective of this study was to identify small molecule compounds as candidates for anti-cancer drug development. We first used cell proliferation and cytotoxicity assays to identify compounds exhibiting anti-cancer activity in vitro in a leukemia cell line (K562). Six top compounds selected from the initial screening of a library of 2,560 compounds were further evaluated in multiple cancer cell lines to rank the drug candidates. The top candidate was further investigated to elucidate the molecular mechanism underlying its anticancer activity. Our studies suggest that this piperazine derivative effectively (GI50 = 0.06-0.16 μM) inhibits cancer cell proliferation and induces caspase-dependent apoptosis via inhibiting multiple cancer signaling pathways including the PI3K/AKT, the Src family kinases and the BCR-ABL pathways.


The transactivation function of the Pea3 subfamily Ets transcription factors is regulated by sumoylation.
Pea3, an Ets transcriptional factor, comprises multiple regulatory domains that affect its DNA binding and transcriptional activation. The aim of this work is to uncover the mechanism of action of negative regulatory regions flanking the transactivation domain. Mutagenesis of amino acid residues in the C-terminal negative regulatory region for transactivation revealed critical residues, including a lysine residue, K96, required for its function. Corresponding mutations in the closely related Pea3 subfamily members, Erm and Er81, also dramatically increased the transactivation capacity of their activation domains. Interestingly, all three proteins are sumoylated at this conserved lysine residue. Pea3 contains four other lysines, K222, K256, K318, and K437, embedded in a perfect SUMO consensus motif. The contribution of these lysine residues to the regulation of Pea3 activity and their sumoylation pattern was explored using a GAL4-PEA3 chimera devoid of the ETS DNA-binding domain and by analyzing the native protein. All four candidate SUMO sites included in the GAL4-PEA3 chimera were modified by sumoylation, and their simultaneous mutation dramatically increased the transactivation potential of Pea3. Similar analysis of full-length Pea3 confirmed K96, K222, and K256 as major SUMO modification sites. Collectively, these observations suggest that the activity of Pea3 and its paralogs, Erm and Er81, is negatively regulated by sumoylation.


Development and validation of 11 symptom indexes to evaluate response to chemotherapy for advanced cancer.
Recent guidance from the FDA discusses patient-reported outcomes as end points in clinical trials. Using methods consistent with this guidance, the authors developed symptom indexes for patients with advanced cancer. Input on the most important symptoms was obtained from 533 patients recruited from NCCN Member Institutions and 4 nonprofit social service organizations. Diagnoses included bladder, brain, breast, colorectal, head and neck, hepatobiliary/pancreatic, kidney, lung, ovarian, and prostate cancers and lymphoma. Physician experts in each of these diseases were also surveyed to differentiate symptoms that were predominantly disease-based from those that were predominantly treatment-induced. Results are evaluated alongside previously published indexes for 9 of these 11 advanced cancers that were created based on expert provider surveys, also implemented at NCCN Member Institutions. Final results are 11 symptom indexes that reflect the highest priorities of people affected by these 11 advanced cancers and the experienced perspective of the people who provide their medical treatment. Beyond the clinical value of such indexes, they may also contribute significantly to satisfying regulatory requirements for a standardized tool to evaluate drug efficacy with respect to symptomatology.


Tensions within management roles in healthcare organisations.
Aim This article reports the results of a study that gives an insight into ward leaders' perspectives of their leadership role and explores how they deliver leadership at ward level within organisational constraints and processes. Previous studies have been evaluations of clinical leadership in general, or literature reviews of the ward leader role. The aim of this study was to examine the leadership role of ward sisters and to understand how they lead improvements in quality of care on their wards. Methods A qualitative methodology was used, incorporating 19 in-depth interviews with ward leaders and modern matrons. Results Three main themes were identified: empty conformity, authority and autonomy, and visibility and leading by example. Participants aimed to be role models in leading and maintaining standards of care for patients, but this was sometimes constrained by organisational processes, lack of authority and autonomy, and lack of support and preparation. Conclusion Perceived differences between nursing and health service management mean that ward leaders' efforts to lead improvements in quality care are often undermined. Ward leaders must strike a balance between leading high-quality nursing care, in the context of organisational and political performance requirements, and the demands of administrative work, while often lacking autonomy and authority.


Impact of the revised (2008) EORTC/MSG definitions for invasive fungal disease on the rates of diagnosis of invasive aspergillosis.
Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications.


Immunotherapy of hematologic malignancy.
Over the past few years, improved understanding of the molecular basis of interactions between antigen presenting cells and effector cells and advances in informatics have both led to the identification of many candidate antigens that are targets for immunotherapy. However, while immunotherapy has successfully eradicated relapsed hematologic malignancy after allogeneic transplant as well as virally induced tumors, limitations have been identified in extending immunotherapy to a wider range of hematologic malignancies. This review provides an overview of three immunotherapy strategies and how they may be improved. In Section I, Dr. Stevenson reviews the clinical experience with genetic vaccines delivered through naked DNA alone or viral vectors, which are showing promise in clinical trials in lymphoma and myeloma patients. She describes efforts to manipulate constructs genetically to enhance immunogenicity and to add additional elements to generate a more sustained immune response. In Section II, Dr. Molldrem describes clinical experience with peptide vaccines, with a particular focus on myeloid tissue-restricted proteins as GVL target antigens in CML and AML. Proteinase 3 and other azurophil granule proteins may be particularly good targets for both autologous and allogeneic T-cell responses. The potency of peptide vaccines may potentially be increased by genetically modifying peptides to enhance T-cell receptor affinity. Finally, in Section III, Dr. Heslop reviews clinical experience with adoptive immunotherapy with T cells. Transferred T cells have clinical benefit in treating relapsed malignancy post transplant, and Epstein-Barr virus associated tumors. However, T cells have been less successful in treating other hematologic malignancies due to inadequate persistence or expansion of adoptively transferred cells and the presence of tumor evasion mechanisms. An improved understanding of the interactions of antigen presenting cells with T cells should optimize efforts to manufacture effector T cells, while manipulation of lymphocyte homeostasis in vivo and development of gene therapy approaches may enhance the persistence and function of adoptively transferred T cells.


A case reopened: teleology and its consequences for the units of selection discussion.
Darwinian explanations for teleology are often imprecise, and justify the occurrence of teleological features by referring to natural selection in a vague and unspecified sense. In this paper, the Darwinian account for teleology is further analyzed. It is argued that in theory only a specific form of teleology--teleology that is caused by and directed towards the preservation of the genetic program--can be explained in a naturalistic way by employing Darwin's theory of natural selection. This observation links teleology with the units of selection discussion, as for both discussions the end-direction of teleological processes and behavior is of elementary importance. According to Dawkins' analysis, the unit of selection is an active germ-like replicator with a sufficient degree of longevity-fecundity-copying fidelity. From the teleological point of view, the unit of selection should additionally incorporate the genetic program in order to naturalize teleology. It is shown that within sexually reproducing species these two requirements cannot be met. Dawkins' concept of genic selectionism cannot be maintained without violating the naturalistic claims on teleology, and none of the other frequently proposed unit of selection candidates can adequately meet the demands as developed by Dawkins and those developed in the light of teleology.


[The prevalence of abdominal tuberculosis and the specific features of its detection].
A hundred and thirteen case histories of patients with isolated and generalized forms of abdominal tuberculosis were analyzed. The patients' age was 15 to 79 years; there were 86 (76.1%) males and 27 (23.9%) females. The patients were admitted more frequently from other tuberculosis facilities (66.7%) and less frequently from general hospitals (33.3%). In 62 (54.9%) cases, abdominal tuberculosis showed a complicated course. The residents of Moscow and its region, predominantly the unemployed (85.8%), prevailed in the structure of detected patients with abdominal tuberculosis. In the period of 2001 to 2004, there was a rise in the incidence of new-onset abdominal tuberculosis, its rate increased from 4.4 (2001) to 8.3% (2004) of the total number of patients admitted to Moscow clinical hospital No. 7 for extrapulmonary tuberculosis admitted. This gives no way of considering this site of tuberculosis to be rare. In the structure of abdominal tuberculosis, its generalized forms were prevalent (86.7%), which was associated with the late detection of abdominal tuberculosis and the significant increase in the number of HIV-infected patients from 14.3 (2000) to 33.3% (2004). Abdominal organ lesions were more frequently observed in severe generalized pulmonary processes, such as disseminated (45.1%), infiltrative (18.6%) or fibrocavernous (15.9%) tuberculosis. An algorithm of diagnosis of abdominal tuberculosis and the rates of its detection by various studies are presented in the paper. Abdominal tuberculosis was diagnosed in 8.9% of cases by noninvasive comprehensive examination methods, in 18.6% by laparoscopy, and in most cases (57.5%) intraoperatively. In socially dysadapted persons, postmortem abdominal tuberculosis was detected in 15% of cases.


Strategies for developing a family support group.
Various interventions may be used by nurses to provide social support to critical care families. Nurses may support family members in one-to-one relationships, or by facilitating the development of supportive relationships in the group setting. The steps described here are fundamental in developing a support group for family members of adults hospitalized in a surgical ICU to meet their predetermined needs. The support needs of family members and the timing of a support group during the critical care phase must first be validated. Once this assessment is completed, the support group may be based on the educational model, mutual-peer support model, educational-mutual support model, or ventilation model. The group model selected will provide direction to the structure, membership, and leadership of the support group. Regardless of the model considered appropriate for the needs of the family population and setting, critical care nurses need to evaluate the impact of the support group on the psychologic health of the family. The four different group perspectives clearly illustrate the need for nurses to determine what types of support are needed or are most beneficial for families during various phases of illness. Perhaps family members benefit from sharing and camaraderie during the acute or critical care phase, whereas educational support groups are more effective in reviewing illness and treatment implications after the immediate threat of the illness has passed. Findings from these evaluation studies will assist nurses in shaping intervention strategies for critical care family members in clinical practice.


Higher parity associated with higher risk of death from gastric cancer.
To examine the association between parity and gastric cancer (the cases are almost all premenopausal women) risk in a cohort of young parous women. The study cohort consisted of all women with a record of a first and singleton childbirth in the Birth Register between 1978 and 1987. We tracked each woman from the time of her first childbirth to December 31, 2008. Their vital status was ascertained by linking records to the computerized mortality database. Cox proportional hazard regression models were used to estimate hazard ratios of death from gastric cancer associated with parity. There were 1090 gastric cancer deaths (85.87% of them were premenopausal) during 33 686 828 person-years of follow-up. The mortality rate of gastric cancer was 3.24 cases per 100,000 person-years. A trend of increasing risk of gastric cancer was seen with increasing parity. The adjusted hazard ratio was 1.24 [confidence interval (95% CI): 1.02-1.50] for women who had borne two to three children, and 1.32 (95% CI: 1.01-1.72) for women with four or more births, when compared with women who had given birth to only one child. These results suggest that higher parity may increase the risk of death from gastric cancer among premenopausal women.


In vitro whole-genome analysis identifies a susceptibility locus for HIV-1.
Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1-infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)-anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents.


Identification of the source of Francisella tularensis infection by multiple-locus variable-number tandem repeat analysis.
Tularemia is a zoonotic disease caused by Francisella tularensis. Most patients in Japan have reportedly acquired such infections through direct contact with infected Japanese hares. We recently encountered a patient who contracted tularemia after skinning and butchering a dead hare. Because the remains of the hare were available, we attempted to determine whether the patient actually contracted infection by handling the carcass. F. tularensis-specific sequences were successfully amplified by PCR from the patient specimens as well as from the remnants of discarded hare carcass. PCR amplification of the ISFtu2 and RD1 regions indicated infection by F. tularensis subsp. holarctica, which was considered as a prevalent strain in Japan. Furthermore, high-resolution multiple-locus variable-number tandem repeat analysis (MLVA) showed that the combination of repeat numbers in sequences from the patient and hare were indistinguishable, thus indicating that the patient had been infected with F. tularensis strain that had also infected the hare. These findings demonstrated that MLVA is a useful epidemiological investigational tool to identify possible sources of certain zoonotic diseases such as tularemia.


Anti-science kills: From Soviet embrace of pseudoscience to accelerated attacks on US biomedicine.
The United States witnessed an unprecedented politicization of biomedical science starting in 2015 that has exploded into a complex, multimodal anti-science empire operating through mass media, political elections, legislation, and even health systems. Anti-science activities now pervade the daily lives of many Americans, and threaten to infect other parts of the world. We can attribute the deaths of tens of thousands of Americans from COVID-19, measles, and other vaccine-preventable diseases to anti-science. The acceleration of anti-science activities demands not only new responses and approaches but also international coordination. Vaccines and other biomedical advances will not be sufficient to halt COVID-19 or future potentially catastrophic illnesses, unless we simultaneously counter anti-science aggression.


Consumers' Opinions towards Public Health Effects of Online Games: An Empirical Study Based on Social Media Comments in China.
Online game products have fueled the boom in China's digital economy. Meanwhile, its public health concerns have sparked discussion among consumers on social media. However, past research has seldom studied the public health topics caused by online games from the perspective of consumer opinions. This paper attempts to identify consumers' opinions on the health impact of online game products through non-structured text and large-size social media comments. Thus, we designed a natural language processing (NLP) framework based on machine learning, which consists of topic mining, multi-label classification, and sentimental analysis. The hierarchical clustering method-based topic mining procedure determines the compatibility of this study and previous research. Every three topics are identified in "Personal Health Effects" and "Social Health Effects", respectively. Then, the multi-label classification model's results show that 61.62% of 327,505 comments have opinions about the health effects of online games. Topics "Adolescent Education" and "Commercial Morality" occupy the top two places of consumer attention. More than 31% of comments support two or more topics, and the "Adolescent Education" and "Commercial Morality" combination also have the highest co-occurrence. Finally, consumers expressed different emotional preferences for different topics, with an average of 63% of comments expressing negative emotions related to the health attributes of online games. In general, Chinese consumers are most concerned with adolescent education issues and hold the strongest negative emotion towards the commercial morality problems of enterprises. The significance of research results is that it reminds online game-related enterprises to pay attention to the potential harm to public health while bringing about additional profits through online game products. Furthermore, negative consumer emotions may cause damage to brand image, business reputation, and the sustainable development of the enterprises themselves. It also provides the government supervision departments with an advanced analysis method reference for more effective administration to protect public health and promote the development of the digital economy.


Training to use a commercial brain-computer interface as access technology: a case study.
This case study describes how an individual with spastic quadriplegic cerebral palsy was trained over a period of four weeks to use a commercial electroencephalography (EEG)-based brain-computer interface (BCI). The participant spent three sessions exploring the system, and seven sessions playing a game focused on EEG feedback training of left and right arm motor imagery and a customised, training game paradigm was employed. The participant showed improvement in the production of two distinct EEG patterns. The participant's performance was influenced by motivation, fatigue and concentration. Six weeks post-training the participant could still control the BCI and used this to type a sentence using an augmentative and alternative communication application on a wirelessly linked device. The results from this case study highlight the importance of creating a dynamic, relevant and engaging training environment for BCIs. Implications for Rehabilitation Customising a training paradigm to suit the users' interests can influence adherence to assistive technology training. Mood, fatigue, physical illness and motivation influence the usability of a brain-computer interface. Commercial brain-computer interfaces, which require little set up time, may be used as access technology for individuals with severe disabilities.


[Bacterial population dynamics in a soil--plant system].
The dynamics of Rhizobium leguminosarum and Arthrobacter crystallopoietes populations introduced into soil at different levels of density was studied in a zone near barley roots. Microbial life with a high rate of growth was found only at the root surface. For A. crystallopoietes, the ultimate bacterial incidence at the root surface was found to depend on the original level of population density. For Rh. leguminosarum, the ultimate incidence was shown to reach an identical level irrespective of the original population density. Apparently, the identical level of stabilization in Rh. leguminosarum and the dependence of the ultimate incidence of A. crystallopoietes on the original population density reflect the peculiarities of ecological strategies displayed by these microorganisms. The introduction of A. crystallopoietes and Rh. leguminosarum into soil had no effect on the dynamics of soil bacteria assayed by the inoculation method.


Neurons expressing neuropeptide Y mRNA in the infundibular hypothalamus of Japanese quail are activated by fasting and co-express agouti-related protein mRNA.
The neural mechanisms involved in the compensatory hyperphagia exhibited by many vertebrate species after a fast are not fully understood but, in mammals, appear to involve nutritionally-sensitive neurons that co-express neuropeptide Y (NPY) and agouti-related protein (AGRP) in the infundibular hypothalamus. We investigated whether these neurons have been evolutionarily conserved in a non-mammalian vertebrate, the Japanese quail. Birds exhibited compensatory hyperphagia 1 h after return of food following a 24-h fast. We addressed a potential regulatory role for NPY, first, by using in situ hybridisation (ISH) to map NPY gene expression in the hypothalamus. This revealed a strong signal in the infundibular nucleus (IN). Secondly, we quantified NPY gene expression in 24-h fasted birds compared to ad libitum fed controls using two independent methods. In whole hypothalamus, measured by ribonuclease protection assay, NPY mRNA increased 1.5-fold in fasted birds. A similar, 1.7-fold, increase was observed specifically in the IN when analysed by ISH. No differences in NPY expression between fed and fasted birds were observed in other brain regions. To determine whether NPY neurons in the avian IN co-express AGRP, we cloned a fragment of the quail AGRP gene and used it to localise AGRP mRNA by ISH. The gene was expressed exclusively in the hypothalamus, specifically in the IN, where its distribution matched that of NPY. Double-label ISH revealed that the majority of NPY neurons in the IN co-express AGRP mRNA. Collectively, these data indicate that this cell type has been neuroanatomically and functionally conserved during vertebrate evolution.


Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization.
A recent study--comparing those with depression, somatization, comorbid depression+somatization, and controls--showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G-protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway-both centrally and peripherally-driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (γ-mangostin), N-acetyl cysteine, and pamoic acid.


Health beliefs and attitudes associated with HPV vaccine intention among young gay and bisexual men in the Southeastern United States.
Gay and bisexual men are at increased risk of anal cancer as a result of human papillomavirus (HPV) infection. Prophylactic vaccination is a potentially effective strategy for preventing anal cancer in this population. The purpose of this study was to identify factors associated with gay and bisexual men's intention to receive HPV vaccine. In the fall of 2010, 179 self-identified gay and bisexual men (mean age 22 years) completed an Internet-based questionnaire assessing beliefs and attitudes toward HPV vaccination. Men were recruited from college-based and Internet venues throughout the southeastern United States. The probability of intent to receive HPV vaccine was modeled using logistic regression. A majority of men (93%) had heard of HPV prior to participation but were generally unaware of the association of HPV with anal, penile, and oral cancers. Only 26% were aware of an HPV vaccine for males. Of the 179 participants, 64 (36%) were likely to be vaccinated. Men most likely to receive HPV vaccine perceived stronger physical and psychological benefits from vaccination and had more positive attitudes toward the vaccine. Conversely, intent to be vaccinated was negatively associated with concern over the financial cost of vaccination. Findings from this study can inform college-based health education programs aimed at increasing vaccine uptake among gay and bisexual men.


Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1.
Oncogenic Epstein-Barr virus (EBV) uses various approaches to escape host immune responses and persist in B cells. Such persistent infections may provide the opportunity for this virus to initiate tumor formation. Using EBV-immortalized lymphoblastoid cell lines (LCLs) as a model, we found that the expression of major histocompatibility complex (MHC) class II and CD74 in B cells is repressed after EBV infection. Class II transactivator (CIITA) is the master regulator of MHC class II-related genes. As expected, CIITA was downregulated in LCLs. We showed that downregulation of CIITA is caused by EBV latent membrane protein 2A (LMP2A) and driven by the CIITA-PIII promoter. Furthermore, we demonstrated that LMP2A-mediated E47 and PU.1 reduction resulted in CIITA suppression. Mechanistically, the LMP2A immunoreceptor tyrosine-based activation motif was critical for the repression of E47 and PU.1 promoter activity via Syk, Src, and the phosphatidylinositol 3-kinase/Akt pathway. Elimination of LMP2A in LCLs using a shLMP2A approach showed that the expression levels of E47, PU.1, CIITA, MHC class II, and CD74 are reversed. These data indicated that the LMP2A may reduce MHC class II expression through interference with the E47/PU.1-CIITA pathway. Finally, we demonstrated that MHC class II may be detected in tonsils and EBV-negative Hodgkin disease but not in EBV-associated posttransplant lymphoproliferative disease and Hodgkin disease.


Euthanasia and Physician-Assisted Suicide in Patients With Multiple Geriatric Syndromes.
The Dutch Regional Euthanasia Review Committees (RTEs) reviewed and reported an increasing number of cases of euthanasia and physician-assisted suicide (EAS) requested by older people with multiple geriatric syndromes (MGS). Knowledge of the characteristics of cases of EAS for MGS is important to facilitate societal debate and to monitor EAS practice. To examine the accumulation of patient characteristics, geriatric syndromes, and other circumstances as reported in the case summaries of the RTEs that led to unbearable suffering associated with a request for EAS and to analyze the RTEs' assessments of these cases of EAS. A qualitative content analysis was conducted of all case summaries filed from January 1, 2013, to December 31, 2019, under the category MGS and published in a national open access database. These case summaries were selected by the RTEs from the total of 1605 reported cases of EAS in the category MGS. The RTEs published 53 cases (41 [77%] female) under the category MGS. A total of 28 patients (53%) had always perceived themselves as independent, active, and socially involved. None of the patients suffered from life-threatening conditions. Multiple geriatric syndromes, such as visual impairment (34 cases [64%]), hearing loss (28 cases [53%]), pain (25 cases [47%]), and chronic tiredness (22 cases [42%]), were common. The request for EAS was often preceded by a sequence of events, especially recurrent falls (33 cases [62%]). Although physical suffering could be determined in all cases, the case descriptions found that suffering occurred on multiple dimensions, such as the loss of mobility (44 [83%]), fears (21 [40%]), dependence (23 [43%]), and social isolation (19 [36%]). This qualitative study suggests that an accumulation of geriatric syndromes leading to a request for EAS is often intertwined with the social and existential dimension of suffering. This leads to a complex interplay of physical, psychological, and existential suffering that changes over time.


Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand?
Mixed cryoglobulinemia (MC) vasculitis represents a complication of the B cell response to a variety of chronic inflammatory diseases. Recent reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes. The goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis. After systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.4%) or essential mixed cryoglobulinemia (24.6%). Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments. Most patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m(2) of rituximab. The duration of follow-up after rituximab therapy was 9.7 months. Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients. A relapse of MC was noted in 14 out of 36 (39%) patients. A relatively small number of side effects were reported. We conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients. A relapse of cryoglobulinemia vasculitis was frequently noted. Randomised controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.


The Nasal Tip Rotation Flap for Reconstruction of the Lateral Nasal Tip, Anterior Ala, and Soft Triangle: The Authors' Experience With 55 Patients.
Defects of the lateral nasal tip, anterior ala, and soft triangle subunits lack reconstructive options that are consistently satisfactory. For such defects, the novel anterior-based nasal tip rotation flap provides functional and aesthetic results in a single operative session. To describe the authors' experience with the nasal tip rotation flap, including patient selection and design modifications to enhance aesthetic success. An IRB-approved retrospective database review of nasal tip rotation flap repairs was performed at the Medical University of South Carolina and Stanford University Medical Center. The design and surgical technique of this flap are described and illustrated, emphasizing factors such as nasal shape and defect location in modifying flap design. The nasal tip rotation is a single-stage, local flap that provides optimal tissue match with recapitulation of the native topography of the nasal tip and incision lines that are well hidden at the junction of cosmetic subunits. The mechanics of the flap distribute closure tension widely across the alar rim without focal notching or airway compromise. The nasal tip rotation flap is a reliable, cosmetically elegant repair that fills a gap in the reconstructive options for anterior ala and soft triangle defects on the nose.