Specific residues of PB2 and PA influenza virus polymerase subunits confer the ability for RNA polymerase II degradation and virus pathogenicity in mice.
Influenza virus transcription requires functional coupling with cellular transcription for the cap-snatching process. Despite this fact, RNA polymerase II (RNAP II) is degraded during infection in a process triggered by the viral polymerase. Reassortant viruses from the A/PR/8/34 (PR8) strain that induce (hvPR8) or do not induce (lvPR8) RNAP II degradation led to the identification of PA and PB2 subunits as responsible for the degradation process. Three changes in the PB2 sequence (I105M, N456D, and I504V) and two in PA (Q193H and I550L) differentiate PA and PB2 of lvPR8 from those of hvPR8. Using recombinant viruses, we observed that changes at position 504 of PB2, together with 550 of PA, confer the ability on lvPR8 for RNAP II degradation and, conversely, abolish hvPR8 degradation capacity. Since hvPR8 is more pathogenic than lvPR8 in mice, we tested the potential contribution of RNAP II degradation in a distant viral strain, the 2009 pandemic A/California/04/09 (CAL) virus, whose PA and PB2 subunits are of avian origin. As in the hvPR8 virus, mutations at positions 504 of PB2 and 550 of PA in CAL virus abolished its RNAP II degradation capacity. Moreover, in an in vivo model, the CAL-infected mice lost more body weight, and 75% lethality was observed in this situation compared with 100% survival in mutant-CAL- or mock-infected animals. These results confirm the involvement of specific PB2 and PA residues in RNAP II degradation, which correlates with pathogenicity in mice of viruses containing human or avian polymerase PB2 and PA subunits. The influenza virus polymerase induces the degradation of RNAP II, which probably cooperates to avoid the antiviral response. Here, we have characterized two specific residues located in the PA and PB2 polymerase subunits that mediate this degradation in different influenza viruses. Moreover, a clear correlation between RNAP II degradation and in vivo pathogenicity in mice was observed, indicating that the degradative process constitutes a viral pathogenicity factor.


The Maryland Quality Indicator Project: searching for opportunities for improvement.
High-quality care is a goal of all health care providers; defining and measuring quality care, however, can be challenging. The Maryland Quality Indicator Project, which began in 1985, helps hospitals in measuring quality within their own institutions. Fifteen in patient and outpatient monitors based on the data provided by participating hospitals are compared. Institutions can then compare their own activity both internally and externally. Definitions for the 15 indicators are provided, as are several examples for applications of these data.


Cannabis Use Among Adults in Cigarette Smoking Cessation Treatment in Ontario, Canada: Prevalence and Association With Tobacco Cessation Outcome, 2015-2021.
Objectives. To examine cannabis use prevalence and its association with tobacco cessation among adults enrolled in cigarette smoking cessation treatment before and after Canada legalized recreational cannabis in October 2018. Methods. The sample comprised 83 206 adults enrolled in primary care-based cigarette smoking cessation treatment between 2015 and 2021 in Ontario, Canada. Past-30-day cannabis use was self-reported at enrollment and cigarette smoking abstinence at 6-month follow-up. Results. Past-30-day prevalence of cannabis use increased from 20.2% in 2015 to 37.7% in 2021. The prevalence increased linearly both before and after legalization. Cannabis and tobacco co-use was associated with lower odds of self-reported cigarette smoking abstinence at 6-month follow-up than tobacco use only (24.4% vs 29.3%; odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.75, 0.81). This association was attenuated after adjustment for covariates (OR = 0.93; 95% CI = 0.89, 0.97) and weakened slightly over time. Conclusions. Cannabis use prevalence almost doubled from 2015 to 2021 among primary care patients in Ontario seeking treatment to quit cigarettes and was associated with poorer quit outcomes. Further research into the impact of cannabis policy on cannabis and tobacco co-use is warranted to mitigate harm. (Am J Public Health. 2024;114(1):98-107. https://doi.org/10.2105/AJPH.2023.307445).


Irreversible Primary Visual Cortex Impairment in a Mouse Model of High-Risk Schizophrenia.
Although visual deficits can be observed at any stage of schizophrenia, few studies have focused on visual cortex alterations in individuals at high risk of schizophrenia. This study aimed to investigate the pathological changes of the primary visual cortex in a prenatal mouse model of MK801-induced high-risk schizophrenia. The high-risk schizophrenia model was generated by MK801 injection into pregnant mice. The male offspring without schizophrenia-like behaviors in early adulthood were defined as the high-risk mouse model of schizophrenia (HRMMS) and divided into two groups. One HRMMS group received the antipsychotic agent risperidone beginning at postnatal week 4 and another group did not receive any treatment. After treatment for 4 weeks, in vivo two-photon calcium imaging was performed to characterize the primary visual cortex activity. The novel object recognition test and the prepulse inhibition apparatus test were also implemented to assess the cognitive and behavioral performance, respectively. Both groups of HRMMS mice, with or without antipsychotic treatment, had decreased neuronal calcium activity, demonstrating primary visual cortex impairment. More notably, antipsychotic treatment did not normalize the impaired neuronal activities in the primary visual cortex. Correspondingly, the treatment did not improve the cognitive or behavioral impairment. Visual cortex impairment might be a prominent feature of individuals at high risk of schizophrenia that cannot be normalized by early treatment with antipsychotic medication, indicating the presence of independent regulatory pathways for visual perception disturbance in schizophrenia. Thus, visual system impairment in schizophrenic patients must be further studied.


Numerical Simulation of Mandible Bone Remodeling under Tooth Loading: A Parametric Study.
Bone adapts to the change of mechanical stimulus by bone remodeling activities. A number of numerical algorithms have been developed to model the adaptive bone remodeling under mechanical loads for orthopedic and dental applications. This paper examines the effects of several model parameters on the computed apparent bone density in mandible under normal chewing and biting forces. The density change rate was based on the strain energy density per unit mass. The algorithms used in this study containing an equilibrium zone (lazy zone) and saturated values of density change rate provides certain stability to result in convergence without discontinuous checkerboard patterns. The parametric study shows that when different boundary conditions were applied, the bone density distributions at convergence were very different, except in the vicinity of the applied loads. Compared with the effects of boundary conditions, the models are less sensitive to the choice of initial density values. Several models starting from different initial density values resulted in similar but not exactly the same bone density distribution at convergence. The results also show that higher reference value of mechanical stimulus resulted in lower average bone density at convergence. Moreover, the width of equilibrium zone did not substantially affect the average density at convergence. However, with increasing width, the areas with the highest and the lowest bone density areas were all reduced. The limitations of the models and challenges for future work were discussed for the better agreement between the computed results and the in vivo data.


Population genomic analysis of Tunisian Medicago truncatula reveals candidates for local adaptation.
Genome-wide association studies rely upon segregating natural genetic variation, particularly the patterns of polymorphism and correlation between adjacent markers. To facilitate association studies in the model legume Medicago truncatula, we present a genome-scale polymorphism scan using existing Affymetrix microarrays. We develop and validate a method that uses a simple information-criteria algorithm to call polymorphism from microarray data without reliance on a reference genotype. We genotype 12 inbred M. truncatula lines sampled from four wild Tunisian populations and find polymorphisms at approximately 7% of features, comprising 31 419 probes. Only approximately 3% of these markers assort by population, and of these only 10% differentiate between populations from saline and non-saline sites. Fifty-two differentiated probes with unique genome locations correspond to 18 distinct genome regions. Sanger resequencing was used to characterize a subset of maker loci and develop a single nucleotide polymorphism (SNP)-typing assay that confirmed marker assortment by habitat in an independent sample of 33 individuals from the four populations. Genome-wide linkage disequilibrium (LD) extends on average for approximately 10 kb, falling to background levels by approximately 500 kb. A similar range of LD decay was observed in the 18 genome regions that assort by habitat; these LD blocks delimit candidate genes for local adaptation, many of which encode proteins with predicted functions in abiotic stress tolerance and are targets for functional genomic studies. Tunisian M. truncatula populations contain substantial amounts of genetic variation that is structured in relatively small LD blocks, suggesting a history of migration and recombination. These populations provide a strong resource for genome-wide association studies.


Children Who are Anxious in Silence: A Review on Selective Mutism, the New Anxiety Disorder in DSM-5.
Selective mutism (SM) is a relatively rare childhood disorder characterized by a consistent failure to speak in specific settings (e.g., school, social situations) despite speaking normally in other settings (e.g., at home). The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) lists SM among the anxiety disorders. This makes sense as the current review of the literature confirms that anxiety is a prominent symptom in many children suffering from this condition. Further, research on the etiology and treatment of SM also corroborates the conceptualization of SM as an anxiety disorder. At the same time, critical points can be raised regarding the classification of SM as an anxiety disorder. We explore a number of such issues in this review. Recommendations for dealing with this diagnostic conundrum are made for psychologists, psychiatrists, and other mental health workers who face children with SM in clinical practice, and directions for future research are highlighted.


Spinal Cord Stimulation for Neuropathic Pain Treatment in Brachial Plexus Avulsions: A Literature Review and Report of Two Cases.
At least 50% of individuals who suffer a brachial plexus avulsion (BPA) will develop chronic pain, frequently more debilitating than their functional limitations. Similar to other neuropathic pain states, BPA pain is often refractory to pharmacological agents. Despite spinal cord stimulation (SCS) first being used for BPA in 1974, there have been no published literature reviews examining the current evidence of SCS for the treatment of neuropathic pain following BPA. In addition to a clinical review of the literature for this indication, we also share our experience with high-frequency SCS (HF-SCS) for BPA-related pain. MEDLINE and EMBASE databases were searched. All published articles including at least one BPA individual treated with SCS for pain treatment were included. The initial search identified 288 articles, of which 13 met inclusion criteria for a total of 41 patients. These patients were primarily male and underwent SCS with reported improved pain scores. HF-SCS leads were percutaneously placed in two male patients who suffered BPA from traumatic injuries. At follow-ups of 13 and eight months, respectively, both patients continued to report an improvement in their pain. Despite published reports showing benefit for pain control in patients with BPA, the overall low quality, retrospective evidence included in this review highlights the need for a rigorous prospective study to further address this indication.


Sex as a prognostic factor in gastric cancer.
The aim of this study was to assess whether survival of gastric cancer patients differed between males and females. Although it is well known that the incidence of gastric cancer is higher for men than for women, the existence of a sex-specific prognosis has seldom been addressed. Studies based on population registries have not assessed the role of stage and histology. Cases of histologically confirmed gastric carcinoma were obtained from three Spanish hospitals in Soria (n = 405), Barcelona (n = 249) and Mataró (n = 197). Differences in possible confounders were tested between men and women and survival analyses were performed separately by hospital. Cox's proportional hazards models were used to account for age, tumour stage, histology and tumour sub-location. Only in Mataró was a significant difference in the stage distribution observed between women and men, with a lower proportion of local stage tumours among women (P = 0.047). No statistically significant differences of histological type between men and women were observed in any of the centres. After adjusting for tumour stage and age, women were observed to have significantly better survival in Barcelona (female to male hazard ratio (HR) = 0.578, P < 0.001); this effect was marginal in Soria (HR = 0.788, P = 0.092) and non-significant in Matar-o (HR = 0.895, P = 0.54). Age-adjusted hazard ratios were calculated within each tumour stage. For Barcelona, the effect of better prognosis among women was most marked at local stage (HR = 0.320, P = 0.013), and in Soria at the regional stage (HR = 0.426, P = 0.002). Although in Mataró all HRs were below unity, none were statistically significant. Little effect was observed at the disseminated stage. The other covariables exerted no influence. Women appear to have a better prognosis than men, and the difference could be tumour stage dependent. Confirmation of these findings would give a valuable insight into gastric cancer growth and ultimately be of use in planning treatment.


Archaea-First and the Co-Evolutionary Diversification of Domains of Life.
The origins and evolution of the Archaea, Bacteria, and Eukarya remain controversial. Phylogenomic-wide studies of molecular features that are evolutionarily conserved, such as protein structural domains, suggest Archaea is the first domain of life to diversify from a stem line of descent. This line embodies the last universal common ancestor of cellular life. Here, we propose that ancestors of Euryarchaeota co-evolved with those of Bacteria prior to the diversification of Eukarya. This co-evolutionary scenario is supported by comparative genomic and phylogenomic analyses of the distributions of fold families of domains in the proteomes of free-living organisms, which show horizontal gene recruitments and informational process homologies. It also benefits from the molecular study of cell physiologies responsible for membrane phospholipids, methanogenesis, methane oxidation, cell division, gas vesicles, and the cell wall. Our theory however challenges popular cell fusion and two-domain of life scenarios derived from sequence analysis, demanding phylogenetic reconciliation. Also see the video abstract here: https://youtu.be/9yVWn_Q9faY.


A close examination of trait reactance and issue involvement as moderators of psychological reactance theory.
This study used psychological reactance theory (PRT) to investigate (a) the effectiveness of 2 message features (freedom-threatening language and character frame) and (b) the role of trait reactance and issue involvement as moderators of a perceived freedom threat. Within the context of organ donation, the results indicated no differences for character frame among the donor, recipient, or waiting list narratives. However, freedom-threatening language was positively associated with a perceived freedom threat. In turn, a perceived freedom threat was positively associated with state reactance, which was inversely, albeit nonsignificantly, associated with organ donation attitudes. Attitudes predicted intentions to be an organ donor. Results also revealed that trait reactance was positively associated with a perceived freedom threat. Although not associated with a freedom threat, issue involvement was positively associated with organ donation attitudes and intent to be a donor. Additionally, a trait reactance by issue involvement by freedom-threatening language interaction predicted a perceived freedom threat. Results are discussed with an emphasis on these moderators in PRT.


Tibial lengthening: extraarticular calcaneotibial screw to prevent ankle equinus.
Between 2003 and 2006, we used an extraarticular, cannulated, fully threaded posterior calcaneotibial screw to prevent equinus contracture in 10 patients (four male and six female patients, 14 limbs) undergoing tibial lengthening with the intramedullary skeletal kinetic distractor. Diagnoses were fibular hemimelia (two), mesomelic dwarfism (two), posteromedial bow (one), hemihypertrophy (one), poliomyelitis (one), achondroplasia (one), posttraumatic limb-length discrepancy (one), and hypochondroplasia (one). Average age was 24.5 years (range, 15-54 years). The screw (length, typically 125 mm; diameter, 7 mm) was inserted with the ankle in 10 degrees dorsiflexion. Gastrocnemius soleus recession was performed in two patients to achieve 10 degrees dorsiflexion. Average lengthening was 4.9 cm (range, 3-7 cm). Screws were removed after a mean 3.3 months (range, 2-6 months). Preoperative ankle range of motion was regained within 6 months of screw removal. No neurovascular complications were encountered, and no patients experienced equinus contracture. We also conducted a cadaveric study in which one surgeon inserted screws in eight cadaveric legs under image intensifier control. The flexor hallucis longus muscle belly was the closest anatomic structure noted during dissection. The screw should be inserted obliquely from upper lateral edge of the calcaneus and aimed lateral in the tibia to avoid the flexor hallucis longus muscle. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Relationship between skill training and skill transfer through the example of bimanual motor learning.
Skill training aims to improve the performance of the task at hand and aims to transfer the acquired skill to related tasks. Both skill training and skill transfer are part of our everyday lives, and essential for survival, and their importance is reflected in years of research. Despite these enormous efforts, however, the complex relationship between skill training and skill transfer is not yet portrayed completely. Building upon two theories, we probed this relationship through the example of bimanual learning with a large cross-sectional design (N = 450) using an online framework. We designed five training tasks which differed in the variance of the training material (schema theory) and three transfer tasks differing in their similarity to the training task (identical elements theory). Theoretically, the five training tasks and the three transfer tasks varied approximately linearly from each other. Empirical data, however, suggested merely the presence of three statistically different training tasks and two significantly different transfer tasks, indicating a nonlinear relationship. Against our expectation, Bayesian statistics suggested that the type of skill training was not related to the type of skill transfer. However, the amount of skill training was positively related to the amount of skill transfer. Together, we showed that motor learning studies can be conducted online. Further, our results shed light on the complex relationship between skill training and skill transfer. Understanding this relationship has wide-ranging practical implications for the general population, particularly for musicians, athletes and patients recovering from injury.


A collagen-glycosaminoglycan scaffold supports adult rat mesenchymal stem cell differentiation along osteogenic and chondrogenic routes.
Adult mesenchymal stem cells have the proclivity to differentiate along multiple lineages giving rise to new bone, cartilage, muscle, or fat. Collagen, a normal constituent of bone, provides strength and structural stability and is therefore a potential candidate for use as a substrate on which to engineer bone and cartilage from their respective mesenchymal-derived precursors. In this study, a collagen- glycosaminoglycan scaffold was used to provide a suitable three-dimensional (3-D) environment on which to culture adult rat mesenchymal stem cells and induce differentiation along the osteogenic and chondrogenic lineages. The results demonstrate that adult rat mesenchymal stem cells can undergo osteogenesis when grown on the collagen-glycosaminoglycan scaffold and stimulated with osteogenic factors (dexamethasone, ascorbic acid, beta-glycerophosphate), as evaluated by the temporal induction of the bone-specific proteins, collagen I and osteocalcin, and subsequent matrix mineralization. The osteogenic factors were coupled to activation of the extracellular-regulated protein kinase (ERK), and this kinase was found to play a role in the osteogenic process. As well as supporting osteogenesis, when the cell-seeded scaffold was exposed to chondrogenic factors (dexamethasone and TGF-1beta), collagen II immunoreactivity was increased, providing evidence that the scaffold can also provide a suitable 3-D environment that supports chondrogenesis.


Survey of psychiatric assessment rooms in UK emergency departments.
Aims and method We aimed to estimate the proportion of UK emergency departments with a psychiatric assessment room and to determine whether such rooms met criteria for conducting high-risk assessments. Liaison psychiatry services were asked whether their hospital had such a room, whether it met the criteria and whether respondents judged it to be sufficiently safe and private. Results Of the 60 emergency departments included in the survey, 23% had a psychiatric assessment room that met all the safety criteria and was judged to be safe and private. Barriers to the establishment of an appropriate facility included it being a low priority for hospital management, a room being used for other purposes, and balancing safety requirements with the creation of a calming environment. Clinical implications Mental illness is a common reason for presentation to emergency departments. Despite national recommendations, this survey indicates that many departments lack a sufficiently safe and private assessment room, which compromises the safety and privacy of patient care.


Peripheral circadian clock rhythmicity is retained in the absence of adrenergic signaling.
The incidence of heart attack and stroke undergo diurnal variation. Molecular clocks have been described in the heart and the vasculature; however it is largely unknown how the suprachiasmatic nucleus (SCN) entrains these peripheral oscillators. Norepinephrine and epinephrine, added to aortic smooth muscle cells (ASMCs) in vitro, altered Per1, E4bp4, and dbp expression and altered the observed oscillations in clock gene expression. However, oscillations of Per1, E4bp4, dbp, and Per2 were preserved ex vivo in the aorta, heart, and liver harvested from dopamine beta-hydroxylase knockout mice (Dbh-/-) that cannot synthesize either norepinephrine or epinephrine. Furthermore, clock gene oscillations in heart, liver, and white adipose tissue phase shifted identically in Dbh-/- mice and in Dbh+/- controls in response to daytime restriction of feeding. Oscillation of clock genes was similarly preserved ex vivo in tissues from Dbh+/- and Dbh-/- chronically treated with both propranolol and terazosin, thus excluding compensation by dopamine in Dbh-/- mice. Although adrenergic signaling can influence circadian timing in vitro, peripheral circadian rhythmicity is retained despite its ablation in vivo.


Investigations into an outbreak of suppurative lymphadenitis with BCG vaccine SSI(®) in Singapore.
From 2011 to 2012, we received an unexpectedly high number of reports of suppurative lymphadenitis following administration of a BCG vaccine used in our childhood vaccination programme in Singapore. We sought to determine the local incidence rates of BCG-associated suppurative lymphadenitis across the 2009 to 2012 vaccinated cohorts, and to analyse the potential factors contributing to this outbreak. Reports of lymphadenitis following BCG vaccination from an AEFI active surveillance system at the KK Women's and Children's Hospital (KKH) and passive surveillance data from other healthcare institutions were reviewed. All valid reports received from January 2009 to December 2013 involving neonates vaccinated with the BCG vaccine in 2009 to 2012 that met case definitions were included in our analysis. Details of the demographics and vaccination history of the child, and statistics from the local vaccination programme were also obtained. Potential contributory factors were selected for further investigation based on a literature review of similar outbreaks overseas. We identified 283 cases of lymphadenitis, of which 76% were suppurative. A spike in suppurative lymphadenitis cases was seen in the 2011 vaccinated cohort, with an incidence rate of 3.16 per 1000 vaccinees, as compared to 0.71 to 0.85 per 1000 in the 2009, 2010 and 2012 cohorts. Our investigations identified the likely cause of the outbreak to be batch-related, arising from manufacturing issues encountered by the manufacturer, after ruling out vaccine administration-related and host-related factors. The three-fold spike in BCG-associated suppurative lymphadenitis cases observed in the 2011 vaccinated cohort, possibly due to batch-to-batch variation of the vaccine, highlights that manufacturing controls can continue to be a challenge. Development of a more sensitive assay to test the reactogenicity of the BCG vaccine may help reduce the occurrence of such outbreaks and improve public confidence in the nation's vaccination programme.


Factors influencing quality of life of Asian breast cancer patients and their caregivers at diagnosis: perceived medical and psychosocial needs.
We aimed to examine the relative importance of medical and psychosocial needs of Asian breast cancer patients and their caregivers, and to identify the determinants of quality of life (QoL) at the time of diagnosis. This is a prospective observational study of the perceived needs and QoL of 99 dyads of breast cancer patients and their caregivers at diagnosis. A self-administered questionnaire was used to measure the perceived importance of medical and psychosocial support needs. Short Form-36 health survey (SF-36) version 2 was used to measure QoL. We also collected patient and caregiver demographic profiles and disease-specific information. Descriptive analysis of perceived needs was performed. SF-36 scores for eight domains and composite scores were calculated. Bivariate analysis and linear regression were performed to identify significant independent predictors of QoL of patients and caregivers. The mean ages of the patients and caregivers were 56.5 years and 51.7 years, respectively. To have family around (73%), prompt information about treatment and treatment options, including side effects (71%), and prompt treatment for side effects (71%) were the top three needs among patients and their caregivers. Supportive nurses and prompt treatment for side effects positively improved patients' social functioning and bodily pain scores. Stage of disease, age, education and ethnicity also influenced QoL. Only the presence of chronic disease influenced caregivers' physical functioning and role-physical scores. Patients and caregivers have similar perceptions of needs at diagnosis. A supportive healthcare team can positively influence patients' QoL, highlighting the importance of tailoring support according to needs.


Regulation of type 1 fimbrial expression in uropathogenic Escherichia coli: heterogeneity of expression through sequence changes in the fim switch region.
Over 80% of uropathogenic Escherichia coli express type 1 fimbriae. Expression is phase variable, and regulation of phase switching can differ between isolates. Previously, this was explained by differences in the expression of the fim recombinases, FimB and FimE. Our study of 50 uropathogenic E. coli isolates confirms variation in the regulation of type 1 fimbriae but, in many cases, the variation could be accounted for by sequence changes within and adjacent to the fim switch, rather than by differences in recombinase expression. This was demonstrated by moving the switch from the isolates into an isogenic background and comparing the switching behaviour with that of the original isolate. Isolates could be arranged into groups based on fim switch regulation and sequence similarity. In certain cases, the altered regulation was located to specific basepair changes within the fim switch. Sequence changes were found that had a marked effect on the activity of either FimB or FimE switching, while others affected FimB switching in only one direction. These results emphasize the value of using naturally selected sequence variation to further the understanding of gene regulation.


Comparing the complications of laparoscopically performed simple, radical and donor nephrectomy
The aim of this study was to compare the complications of laparoscopic simple, radical and donor nephrectomies performed in a single center. The study was conducted on 392 patients who underwent laparoscopic nephrectomy in University of Health Sciences, Ankara Türkiye Yüksek İhtisas Training and Research Hospital between January 1, 2008 and January 30, 2019. Clinical and laboratory parameters were recorded. Postoperative complications were recorded and graded as per Clavien-Dindo classification (CDC). All analyses were performed on SPSS v21.0 (IBM Corp., Armonk, NY, USA). The mean age of the patients was 49.13 ± 15.45 years. The frequency of comorbidities and ASA scores were significantly higher in the laparoscopic radical nephrectomy (LRN) group than in the other groups (P < 0.001). Amount of bleeding was significantly lower in the laparoscopic donor nephrectomy (LDN) group compared to the other groups (P < 0.001). Classification of complications according to CDC showed that complications occurred in 17.01% (n = 25) of the LRN group, 7.02% (n = 12) of the laparoscopic simple nephrectomy (LSN) group, and 2.70% (n = 2) of the LDN group. Length of stay in hospital was significantly higher in the LRN group than in the LSN group (P < 0.001). In this study, the frequency of complications in LRN procedures was found to be higher than the LSN and LDN procedures. Patients with LRN may have more adverse health conditions before the operation. Considering the results of this study, variables such as patient and hospital characteristics, surgeon experience and skills should be evaluated in future studies. In addition, it is important to determine the frequency of complications using a standardized classification in order to enable correct interpretation of results.


Factors associated with low vs increased perceived mastery of clinical work over ten years of practice: a prospective study of Norwegian doctors.
A higher sense of mastery of doctors' clinical work could benefit not only their own mental health but also their work performance and patient care. However, we know little about factors associated with perceived mastery of clinical work among physicians. Our aim was therefore to study characteristics of those with stable low levels and of those with increased levels of mastery over a period of ten years of medical practice. N = 631 doctors were surveyed in their final year of medical school in 1993/94 (T1) and 10 (T2), 15 (T3) and 20 (T4) years later. Low and increased perceived mastery of clinical work were measured between T2, T3 and T4. Response rates for all items measuring low and increased mastery were 238/522 (46%) and 256/522 (49%) respectively. The following explanatory variables were included: demographics, medical school factors, personality and contextual work-related and non-work-related factors. N = 73 (31%) of the doctors reported stable low mastery from T2 to T4. The following variables were significantly associated with low mastery in the adjusted analyses: vulnerability (OR: 1.30, P < .000, CI: 1.12 to 1.50), drinking alcohol to cope with stress during medical school (OR: 2.66, P = .04, CI: 1.03 to 6.85) and social support (OR: 0.78, P = .002, CI: 0.66 to 0.91). N = 39 (15%) reported increased mastery during the ten-year period from T2 to T4. Perceived job demands (OR: 0.66, P = .02, CI: 0.45 to 0.98) and taking up a leading position (OR: 3.04, P = .01, CI: 1.31 to 7.07) were associated with increased mastery after adjustment. Stable low sense of mastery over time is associated with having a vulnerable personality, a history of having used alcohol to cope with stress during medical school and lack of contemporary social support. Conversely, increased sense of mastery is associated with taking up a leading position and having the perception that job demands are decreasing over time. These findings indicate that perceived mastery of clinical work may not be a trait, but a state modifiable over time.


In vitro antimicrobial sensitivity of Neisseria gonorrhoeae from Rwanda.
The in vitro sensitivity of 104 isolates of Neisseria gonorrhoeae to six antimicrobial agents was tested. More than 50% of the isolates produced penicillinase. Of those that did not produce penicillinase, 26% were resistant (minimum inhibitory concentration (MIC)) greater than or equal to 0.5 mg/l), and 68% showed a decreased sensitivity for penicillin G (0.06 less than or equal to MIC less than or equal to 0.25 mg/l). Twenty six per cent and 50% of the strains, respectively, showed a decreased sensitivity to thiamphenicol (MIC greater than or equal to 1 mg/l) and tetracycline (MIC greater than or equal to 2 mg/l). All isolates were sensitive to spectinomycin, kanamycin, and norfloxacin. Of 20 penicillinase producing N gonorrhoeae (PPNG) isolates examined, seven contained the 3.4 megadalton R-plasmid, another seven contained both the 3.4 megadalton and 22.5 megadalton plasmids, five the 4.3 megadalton and 22.5 megadalton plasmids, and one isolate harboured both the 3.4 and 4.3 R-plasmids, together with the 22.5 megadalton plasmid. A disturbing increase in resistance to penicillin has been observed since the publication of earlier surveys, and the clinical implications of these findings are discussed.


Phytochrome D acts in the shade-avoidance syndrome in Arabidopsis by controlling elongation growth and flowering time.
Shade avoidance in higher plants is regulated by the action of multiple phytochrome (phy) species that detect changes in the red/far-red ratio (R/FR) of incident light and initiate a redirection of growth and an acceleration of flowering. The phyB mutant of Arabidopsis is constitutively elongated and early flowering and displays attenuated responses to both reduced R/FR and end-of-day far-red light, conditions that induce strong shade-avoidance reactions in wild-type plants. This indicates that phyB plays an important role in the control of shade avoidance. In Arabidopsis phyB and phyD are the products of a recently duplicated gene and share approximately 80% identity. We investigated the role played by phyD in shade avoidance by analyzing the responses of phyD-deficient mutants. Compared with the monogenic phyB mutant, the phyB-phyD double mutant flowers early and has a smaller leaf area, phenotypes that are characteristic of shade avoidance. Furthermore, compared with the monogenic phyB mutant, the phyB-phyD double mutant shows a more attenuated response to a reduced R/FR for these responses. Compared with the phyA-phyB double mutant, the phyA-phyB-phyD triple mutant has elongated petioles and displays an enhanced elongation of internodes in response to end-of-day far-red light. These characteristics indicate that phyD acts in the shade-avoidance syndrome by controlling flowering time and leaf area and that phyC and/or phyE also play a role.


Exposure to concentrated ambient particles does not affect vascular function in patients with coronary heart disease.
Exposure to fine particulate air pollution is associated with increased cardiovascular morbidity and mortality. We previously demonstrated that exposure to dilute diesel exhaust causes vascular dysfunction in humans. We conducted a study to determine whether exposure to ambient particulate matter causes vascular dysfunction. Twelve male patients with stable coronary heart disease and 12 age-matched volunteers were exposed to concentrated ambient fine and ultrafine particles (CAPs) or filtered air for 2 hr using a randomized, double-blind cross-over study design. We measured peripheral vascular vasomotor and fibrinolytic function, and inflammatory variables-including circulating leukocytes, serum C-reactive protein, and exhaled breath 8-isoprostane and nitrotyrosine-6-8 hr after both exposures. Particulate concentrations (mean +/- SE) in the exposure chamber (190+/-37 microg/m(3)) were higher than ambient levels (31+/-8 microg/m(3)) and levels in filtered air (0.5+/-0.4 microg/m(3); p<0.001). Chemical analysis of CAPs identified low levels of elemental carbon. Exhaled breath 8-isoprostane concentrations increased after exposure to CAPs (16.9+/-8.5 vs. 4.9+/-1.2 pg/mL, p<0.05), but markers of systemic inflammation were largely unchanged. Although there was a dose-dependent increase in blood flow and plasma tissue plasminogen activator release (p<0.001 for all), CAPs exposure had no effect on vascular function in either group. Despite achieving marked increases in particulate matter, exposure to CAPs--low in combustion-derived particles--did not affect vasomotor or fibrinolytic function in either middle-aged healthy volunteers or patients with coronary heart disease. These findings contrast with previous exposures to dilute diesel exhaust and highlight the importance of particle composition in determining the vascular effects of particulate matter in humans.


CASEIN KINASE2-Dependent Phosphorylation of PHOSPHATE2 Fine-tunes Phosphate Homeostasis in Rice.
Plants have evolved complex physiological and biochemical mechanisms to adapt to a heterogeneous soil phosphorus environment. PHOSPHATE2 (PHO2) is a phosphate (Pi) starvation-signaling regulator involved in maintaining Pi homeostasis in plants. Arabidopsis (Arabidopsis thaliana) PHO2 targets PHOSPHATE TRANSPORTER1 (PHT1) and PHO1 for degradation, whereas rice (Oryza sativa) PHO2 is thought to mediate PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1 degradation. However, it is unclear whether and how PHO2 is post-translationally regulated. Here, we show that in rice, the CASEIN KINASE2 (OsCK2) catalytic subunit OsCK2α3 interacts with OsPHO2 in vitro and in vivo in vascular tissues cells, and phosphorylates OsPHO2 at Ser-841. Phosphorylated OsPHO2 is degraded more rapidly than native OsPHO2 in cell-free degradation assays. OsPHO2 interacts with OsPHO1 and targets it for degradation through a multivesicular body-mediated pathway. PHO1 mutation partially rescued the pho2 mutant phenotype. Further genetic analysis showed that a nonphosphorylatable version of OsPHO2 rescued the Ospho2 phenotype of high Pi accumulation in leaves better than native OsPHO2. In addition to the previously established role of OsCK2 in negatively regulating endoplasmic reticulum exit of PHT1 phosphate transporters, this work uncovers a role for OsCK2α3 in modulating Pi homeostasis through regulating the phosphorylation status and abundance of OsPHO2 in rice.


[Psychiatric disorders and psychopathologic manifestations associated with pregnancy and postpartum in Cameroon].
This retrospective study was conducted from Januaty 1, 2002 to May 31, 2004 to ascertain the sociodejnographlc profile of women phychiatric disorders and psychopathologic manifestations during puerperiuni and determine the most common clinical entities at the Jamot Hospital in Yaounde, Cameroon. Study included 40 paturient women who presented psychiatric disorders related to pregnancy, postpartum, abortion, or breastfeeding. Most patients (80%) were less than 34 years of age including 50% under 20 years. Psychiatric disorders were often observed in married women (62.5%) but one of three women (30%) in this study was single. Most of these women (85%) had no income. Primagravid women accounted for 35% of the cohort. Manifestations generally began after delivery (80%) but sometimes appeared during pregnancy (12.5%). A particularly noteworthy finding of this study is the high rate of late postpartum or breastfeeding psychosis. In 40% of cases symptoms appeared between 1 and 6 months after delivery. Acute psychosis was by far the most frequent disorder (77.5%) followed by depression (15%) and manic fits (7.5%). With regard to symbolic representations and social implications, we concur with the Bell people in considering that these manifestations are related to anemia resulting from massive blood loss after delivery. This occurs during the traditional hot water massages performed to eliminate lochia (blood and debris). This sudden blood loss is called "esere meld" in the Ewondo language. In contrast it is considered as lochia retention due to the lack of massage by the Bassa people who use the term "ndjeg gwal" or delivery madness.


A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum.
Tight coordination of gene expression in the developing cerebellum is crucial for establishment of neuronal circuits governing motor and cognitive function. However, transcriptional changes alone do not explain all of the switches underlying neuronal differentiation. Here we unveiled a widespread and highly dynamic splicing program that affects synaptic genes in cerebellar neurons. The motifs enriched in modulated exons implicated the splicing factor Sam68 as a regulator of this program. Sam68 controls splicing of exons with weak branchpoints by directly binding near the 3' splice site and competing with U2AF recruitment. Ablation of Sam68 disrupts splicing regulation of synaptic genes associated with neurodevelopmental diseases and impairs synaptic connections and firing of Purkinje cells, resulting in motor coordination defects, ataxia, and abnormal social behavior. These findings uncover an unexpectedly dynamic splicing regulatory network that shapes the synapse in early life and establishes motor and cognitive circuitry in the developing cerebellum.


Identifying ELIXIR Core Data Resources.
The core mission of ELIXIR is to build a stable and sustainable infrastructure for biological information across Europe. At the heart of this are the data resources, tools and services that ELIXIR offers to the life-sciences community, providing stable and sustainable access to biological data. ELIXIR aims to ensure that these resources are available long-term and that the life-cycles of these resources are managed such that they support the scientific needs of the life-sciences, including biological research. ELIXIR Core Data Resources are defined as a set of European data resources that are of fundamental importance to the wider life-science community and the long-term preservation of biological data. They are complete collections of generic value to life-science, are considered an authority in their field with respect to one or more characteristics, and show high levels of scientific quality and service. Thus, ELIXIR Core Data Resources are of wide applicability and usage. This paper describes the structures, governance and processes that support the identification and evaluation of ELIXIR Core Data Resources. It identifies key indicators which reflect the essence of the definition of an ELIXIR Core Data Resource and support the promotion of excellence in resource development and operation. It describes the specific indicators in more detail and explains their application within ELIXIR's sustainability strategy and science policy actions, and in capacity building, life-cycle management and technical actions. The identification process is currently being implemented and tested for the first time. The findings and outcome will be evaluated by the ELIXIR Scientific Advisory Board in March 2017. Establishing the portfolio of ELIXIR Core Data Resources and ELIXIR Services is a key priority for ELIXIR and publicly marks the transition towards a cohesive infrastructure.


Regional cerebral metabolic rate for glucose and cerebrospinal fluid monoamine metabolites in subacute sclerosing panencephalitis.
Regional cerebral metabolic rate for glucose (rCMRglu) and cerebrospinal fluid monoamine metabolites were measured in two cases of subacute sclerosing panencephalitis (SSPE) with different clinical courses. A marked decrease in rCMRglu was found in the cortical gray matter of a patient with rapidly developing SSPE (3.6-4.2 mg/100 g brain tissue/min). However, the rCMRglu was preserved in the caudate and lenticular nuclei of the patient (7.7 mg/100 g/min). The rCMRglu in a patient with slowly developing SSPE revealed patterns and values similar to those of the control. Cerebrospinal fluid monoamine metabolites; homovanilic acid and 5-hydroxyindoleacetic acid, were decreased in both rapidly and slowly developing SSPE. These data indicated that rCMRglu correlated better with the neurological and psychological status and that dopaminergic and serotonergic abnormalities have been implicated in pathophysiology of SSPE.


Targeting Enterococcus faecalis biofilms with phage therapy.
Phage therapy has been proven to be more effective, in some cases, than conventional antibiotics, especially regarding multidrug-resistant biofilm infections. The objective here was to isolate an anti-Enterococcus faecalis bacteriophage and to evaluate its efficacy against planktonic and biofilm cultures. E. faecalis is an important pathogen found in many infections, including endocarditis and persistent infections associated with root canal treatment failure. The difficulty in E. faecalis treatment has been attributed to the lack of anti-infective strategies to eradicate its biofilm and to the frequent emergence of multidrug-resistant strains. To this end, an anti-E. faecalis and E. faecium phage, termed EFDG1, was isolated from sewage effluents. The phage was visualized by electron microscopy. EFDG1 coding sequences and phylogeny were determined by whole genome sequencing (GenBank accession number KP339049), revealing it belongs to the Spounavirinae subfamily of the Myoviridae phages, which includes promising candidates for therapy against Gram-positive pathogens. This analysis also showed that the EFDG1 genome does not contain apparent harmful genes. EFDG1 antibacterial efficacy was evaluated in vitro against planktonic and biofilm cultures, showing effective lytic activity against various E. faecalis and E. faecium isolates, regardless of their antibiotic resistance profile. In addition, EFDG1 efficiently prevented ex vivo E. faecalis root canal infection. These findings suggest that phage therapy using EFDG1 might be efficacious to prevent E. faecalis infection after root canal treatment.


Synaptonemal complexes analysis in a bull carrying a 4;8 Robertsonian translocation.
Synaptonemal complexes analysis was performed using electron microscopy on surface-spread spermatocytes of a bull heterozygous for the 4;8 Robertsonian translocation. In 19 cells examined, the longest autosomal complex showed kinetochores in a central position whereas the remaining autosomal complexes showed terminal kinetochores. Synapsis in the trivalent appeared complete in all cells, and the trivalents usually showed a CIS configuration. The arm ratio varied from 1.05 to 2.04 with an average of 1.32 +/- 0.43. Out of 47 cells showing X-Y bivalents, 34 showed a small synaptonemal complex at one extremity of the X chromosome, and an unstained gap in the Y chromosome. There was no association between the X-Y bivalent and the trivalent. The absence of association would explain the normal spermatogenesis noted in this bull, in contrast to human and mouse carriers of translocations which show impaired spermatogenesis due to the association between the rearranged chromosomes and the sex vesicle. Further studies involving bulls carrying one or more Robertsonian translocations are needed to determine whether this absence of association is a constant feature in cattle.


Generalizing Evidence from Randomized Trials using Inverse Probability of Sampling Weights.
Results obtained in randomized trials may not easily generalize to target populations. Whereas in randomized trials the treatment assignment mechanism is known, the sampling mechanism by which individuals are selected to participate in the trial is typically not known and assuming random sampling from the target population is often dubious. We consider an inverse probability of sampling weighted (IPSW) estimator for generalizing trial results to a target population. The IPSW estimator is shown to be consistent and asymptotically normal. A consistent sandwich-type variance estimator is derived and simulation results are presented comparing the IPSW estimator to a previously proposed stratified estimator. The methods are then utilized to generalize results from two randomized trials of HIV treatment to all people living with HIV in the United States.


PLA/PLGA nanoparticles for sustained release of docetaxel.
This study investigates the potentiality of nanosphere colloidal suspensions as sustained release systems for intravenous administration of docetaxel (DTX). Nanospheres were prepared by solvent displacement method using polylactic acids (PLA) at different molecular weight and polylactic-co-glycolic (PLGA) as biodegradable matrices. The systems were characterized by light scattering analysis for their mean size, size distribution and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The average diameters of the nanoparticles ranged from 100 to 200 nm. Negative zeta potential values were observed for all systems, particularly the nanospheres produced with the lowest molecular weight PLA showed a zeta potential value of -28mV. Differential scanning calorimetry analysis (DSC) suggested that DTX was molecularly dispersed in the polymeric matrices. A biphasic release of DTX was observed for all colloidal suspensions, after a burst effect in which about 50% (w/w) of the loaded drug was released a sustained release profile for about 10 days was observed. To evaluate the influence of the polymeric carrier on the interaction of DTX with biological membranes, we performed an in vitro study using lipid vesicles made of dipalmitoylphosphatidylcholine (DPPC) as a biomembrane model. DSC was used as a simple and not invasive technique of analysis. DTX produced a depression of DPPC pretransition peak, no variation of the main phase transition temperature and a significative increase of DeltaH value, showing a superficial penetration of the drug into DPPC bilayer. Kinetic experiments demonstrated that the release process of DTX form nanospheres is affected by the molecular weight of the employed polymers.


Linear correlation models for the redox potential of organic molecules in aqueous solutions.
In this study, we use the molecular orbital energy approximation (MOEA) and the energy difference approximation (EDA) to build linear correlation models for the redox potentials of 53 organic compounds in aqueous solutions. The molecules evaluated include nitroxides, phenols, and amines. Both the MOEA and EDA methods yield similar correlation models, however, the MOEA method is less computationally expensive. Correlation coefficients (R2) below 0.3 and mean absolute errors above 0.25 V were found for correlation models built without solvent effects. When explicit water molecules and a continuum solvent model are added to the calculations, correlation coefficients close to 0.8 are reached, and mean absolute errors below 0.18 V are obtained. The incorporation of solvent effects is necessary for good correlation models, particularly for redox processes of charged molecules in aqueous solutions. A comparison of the correlation models from different methodologies is provided. Graphical abstract.


Intraluminal acid activates esophageal nodose C fibers after mast cell activation.
Acid reflux in the esophagus can induce esophageal painful sensations such as heartburn and noncardiac chest pain. The mechanisms underlying acid-induced esophageal nociception are not clearly understood. In our previous studies, we characterized esophageal vagal nociceptive afferents and defined their responses to noxious mechanical and chemical stimulation. In the present study, we aim to determine their responses to intraluminal acid infusion. Extracellular single-unit recordings were performed in nodose ganglion neurons with intact nerve endings in the esophagus using ex vivo esophageal-vagal preparations. Action potentials evoked by esophageal intraluminal acid perfusion were compared in naive and ovalbumin (OVA)-challenged animals, followed by measurements of transepithelial electrical resistance (TEER) and the expression of tight junction proteins (zona occludens-1 and occludin). In naive guinea pigs, intraluminal infusion with either acid (pH = 2-3) or capsaicin did not evoke an action potential discharge in esophageal nodose C fibers. In OVA-sensitized animals, following esophageal mast cell activation by in vivo OVA inhalation, intraluminal acid infusion for about 20 min started to evoke action potential discharges. This effect is further confirmed by selective mast cell activation using in vitro tissue OVA challenge in esophageal-vagal preparations. OVA inhalation leads to decreased TEER and zona occludens-1 expression, suggesting an impaired esophageal epithelial barrier function after mast cell activation. These data for the first time provide direct evidence of intraluminal acid-induced activation of esophageal nociceptive C fibers and suggest that mast cell activation may make esophageal epithelium more permeable to acid, which subsequently may increase esophageal vagal nociceptive C fiber activation.


Protease-like sequence in hepatitis B virus core antigen is not involved in the cleavage processes of core protein in Escherichia coli.
A DNA fragment, coding for hepatitis core antigen (HBcAg), was amplified by polymerase chain reaction and inserted into a lambda PL promoter-derived expression vector. The recombinant plasmid was transformed into Escherichia coli and proteins produced after heat induction were analyzed. In addition to the 21 kDa HBcAg protein, several smaller related polypeptides, particularly one of 17 kDa in size, were also detected with rabbit anti-HBcAg antiserum. Whether the protease-like sequence of core protein involved in the self-cleavage process to form the 17 kDa polypeptide was investigated by a deletion experiment. Our results with a mutant in which 7 amino acids of the conserved protease-like region in the core protein have been deleted suggest that the cleavage does not depend on the presence of these protease-like sequence. In addition, the core protein synthesized from in vitro translation reaction was not cleaved. Core particles from E. coli lysate were purified by sucrose and cesium chloride density gradient centrifugations and subsequently treated with 0.2% of SDS and 0.2% of beta-mecaptoethanol. Immunoblotting analysis, however, did not reveal any conversion of the 21 kDa protein to smaller ones. In conclusion, our results suggest that the protease-like domain at the N-terminus of the core protein does not contain intrinsic autocleavage activity, nor could the HBcAg be converted to smaller antigens by detergent treatment.


Knowledge and Prior Use of HIV Self-Testing in Madrid and Barcelona among Men Who Have Sex with Men More than One Year after Its Legal Authorization in Spain.
This study assessed the knowledge and prior use of HIV self-testing in a sample of men who have sex with men (MSM) recruited in a sexual health clinic and two community-based testing sites in Madrid and Barcelona, >12 months after its legal authorization. Between March 2019 and December 2020, we recruited 2044 MSM. Participants completed a self-administered questionnaire while waiting to be tested for HIV and other STIs. We built two Poisson regression models to assess factors associated with prior knowledge and with use. Among those who had used self-testing in the past we assessed frequency of use and several aspects related to the last testing episode. The proportion of participants that knew about the existence of self-testing and had already used it was of 26.3% and 5.1% respectively. Both, knowledge and use were independently associated with being born in Spain or other western European countries, university education and more recent HIV testing. Additionally, knowledge was associated with older age, having a more favorable economic situation, and not living sexuality in total secrecy. Use was also associated with having received money in exchange for sex. Most (69.5%) reported having self-tested once, 64.8% had self-tested <12 months ago, 63.8% self-tested alone and 71.4% acquired the kit at a pharmacy over the counter. In spite of its authorization and becoming legally available, knowledge and use of HIV self-testing remain low among MSM attending sites specialized in the diagnosis of HIV and other STIs. When designing scale-up strategies, lower levels of knowledge and use in less favored subgroups of MSM need to be factored in.


SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling.
Macropinocytosis is essential for myeloid cells to survey their environment and for growth of RAS-transformed cancer cells. Several growth factors and inflammatory stimuli are known to induce macropinocytosis, but its endogenous inhibitors have remained elusive. Stimulation of Roundabout receptors by Slit ligands inhibits directional migration of many cell types, including immune cells and cancer cells. We report that SLIT2 inhibits macropinocytosis in vitro and in vivo by inducing cytoskeletal changes in macrophages. In mice, SLIT2 attenuates the uptake of muramyl dipeptide, thereby preventing NOD2-dependent activation of NF-κB and consequent secretion of pro-inflammatory chemokine, CXCL1. Conversely, blocking the action of endogenous SLIT2 enhances CXCL1 secretion. SLIT2 also inhibits macropinocytosis in RAS-transformed cancer cells, thereby decreasing their survival in nutrient-deficient conditions which resemble tumor microenvironment. Our results identify SLIT2 as a physiological inhibitor of macropinocytosis and challenge the conventional notion that signals that enhance macropinocytosis negatively regulate cell migration, and vice versa.


Algorithm for the diagnosis and treatment of endoleaks.
Endoluminal grafting of abdominal aortic aneurysms (AAA) has shown promising early results. However, endoleaks present a new and challenging obstacle to successful aneurysm exclusion. We report our experience with primary, persistent endoleaks and provide an algorithm for their diagnosis and management. Over a 19-month period, 73 patients underwent endoluminal repair of their AAAs using a modular bifurcated endograft as part of a US FDA Investigational Device Exemption trial. Spiral computed tomography (CT) scanning was performed prior to discharge after repair to evaluate for complete aneurysm exclusion. If no endoleak was present on that initial CT scan, color-flow duplex scanning was performed at 1 month, with repeat CT scanning at 6 months and 1 year. If the initial CT scan revealed the presence of an endoleak, repeat CT scanning was performed at 2 weeks, 1 month, and 3 months, or until the endoleak resolved. Any patient with an endoleak that persisted beyond 3 months underwent angiographic evaluation to localize the source of the leak. At 1 month, 62 patients (85%) had successful aneurysm exclusion. The remaining 11 patients (15%) had primary endoleaks, 8 (11%) of which persisted beyond 3 months, prompting angiographic evaluation. In 2 patients the endoleak was related to a graft-graft or graft-arterial junction. One was from the endograft terminus in the common iliac artery and was successfully embolized, along with its outflow lumbar artery. The other required placement of an additional endograft component across a leaking graft-graft junction to successfully exclude the aneurysm. The remaining six endoleaks were due to collateral flow through the aneurysm sac. In 4 cases this was lumbar to lumbar flow fed by hypogastric artery collaterals to the inflow lumbar artery. In the remaining 2 patients the endoleak was found to be due to flow between a lumbar and inferior mesenteric artery. Resolution of the endoleak by coil embolization of the feeding hypogastric artery branch in 1 patient was unsuccessful due to rapid recruitment of another hypogastric branch. Two of the six collateral flow endoleaks have resolved spontaneously without treatment, while the remaining cases have been followed up without evidence of aneurysm expansion. Systematic postoperative surveillance facilitates proper diagnosis and treatment of endoleaks. This involves serial CT scans to detect the presence of endoleaks, followed by angiography to determine their etiology and guide treatment, if clinically indicated.


[Targeted epigenetic therapy of cancer. Achievements and perspectives].
In this review, we provide an overview of the physiological and pathophysiological epigenetic changes of normal cells and cancer cells, and emphasize the achievements and the perspectives of cancer epigenetic therapy. Cancer epigenetic alterations correspond foremost to hypermethylation of tumor suppressor genes promotors, global DNA hypomethylation, and overexpression and activity of histone deacetylases. The purpose of epigenetic therapy is to revert the epigenetic alterations in cancer cells and obtain the "normal epigenome" restoration. Epigenetic targets in cancer therapy have focused on HDACs and DNMTs inhibition. The azacitidine and the decitabine, the vorinostat and the romidepsin were approved by US-FDA for treatment of myelodysplastic syndrome, and cutaneous T-cell lymphoma, respectively. Epigenetic and epigenomic changes in single or multiple genes have showed potential impact in cancer as early detection, prognosis and predictive marks. The epigenetic revolution has arrived for biology. The significant progress in epigenetic studies have allowed us, to understand new looks in the physiology and pathophysiology of embryonic development, cancer and other chronic diseases. Specific molecular epigenetic alterations in different cancer types, give us new strategies to design improved cancer therapy. The challenge for epigenetic investigators is design more specific epidrugs with lesser side effects.


Metaproteomics-guided selection of targeted enzymes for bioprospecting of mixed microbial communities.
Hitherto, the main goal of metaproteomic analyses has been to characterize the functional role of particular microorganisms in the microbial ecology of various microbial communities. Recently, it has been suggested that metaproteomics could be used for bioprospecting microbial communities to query for the most active enzymes to improve the selection process of industrially relevant enzymes. In the present study, to reduce the complexity of metaproteomic samples for targeted bioprospecting of novel enzymes, a microbial community capable of producing cellulases was maintained on a chemically defined medium in an enzyme suppressed metabolic steady state. From this state, it was possible to specifically and distinctively induce the desired cellulolytic activity. The extracellular fraction of the protein complement of the induced sample could thereby be purified and compared to a non-induced sample of the same community by differential gel electrophoresis to discriminate between constitutively expressed proteins and proteins upregulated in response to the inducing substance. Using the applied approach, downstream analysis by mass spectrometry could be limited to only proteins recognized as upregulated in the cellulase-induced sample. Of 39 selected proteins, the majority were found to be linked to the need to degrade, take up, and metabolize cellulose. In addition, 28 (72%) of the proteins were non-cytosolic and 17 (44%) were annotated as carbohydrate-active enzymes. The results demonstrated both the applicability of the proposed approach for identifying extracellular proteins and guiding the selection of proteins toward those specifically upregulated and targeted by the enzyme inducing substance. Further, because identification of interesting proteins was based on the regulation of enzyme expression in response to a need to hydrolyze and utilize a specific substance, other unexpected enzyme activities were able to be identified. The described approach created the conditions necessary to be able to select relevant extracellular enzymes that were extracted from the enzyme-induced microbial community. However, for the purpose of bioprospecting for enzymes to clone, produce, and characterize for practical applications, it was concluded that identification against public databases was not sufficient to identify the correct gene or protein sequence for cloning of the identified novel enzymes.


A beta zero-thalassaemia due to a 1605 bp deletion of the 5' beta-globin gene region.
We studied a heterozygous beta zero-thalassaemia patient from Croatia with an unusually high Hb A2 level of 7.6% and an elevated Hb F level of 5.8%. The same condition was found in his father (Hb A2 8.2%; Hb F 8.5%). Gene mapping and direct sequencing analyses revealed a new deletion of 1605 bp in the 5' beta-globin gene region between positions -984/5 and +620/1. This deletion has not been observed among more than 500 beta-thalassaemia chromosomes from the Balkan countries studied in our laboratory.


Physical activity and lung function-Cause or consequence?
Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991-1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999-2003, and ECRHS III in 2010-2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21-95) for forced expiratory volume in one second and 83 mL (36-130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding.


Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group.
Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS. Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients). Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS. RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.


Calvarial fracture patterns on CT imaging predict risk of a delayed epidural hematoma following decompressive craniectomy for traumatic brain injury.
The development of a delayed epidural hematoma as a result of decompressive craniectomy represents an urgent and potentially lethal complication in traumatic brain injury. The goal of this study was to determine the incidence of delayed epidural hematoma and whether patterns of skull fractures on the preoperative CT scan could predict risk of a delayed epidural hematoma. We retrospectively evaluated medical records and imaging studies for patients with acute traumatic brain injury who underwent a decompressive craniectomy during a 9-year period. We compared patterns of skull fractures contralateral to the side of the craniectomy with the occurrence of a postoperative delayed epidural hematoma. In a series of 203 patients undergoing decompressive craniectomy for acute traumatic brain injury, the incidence of a delayed epidural hematoma complication was 6% (12 of 203). All 12 patients who developed a delayed epidural hematoma had a contralateral calvarial fracture on preoperative CT at the site where the delayed epidural hematoma subsequently formed. A contralateral calvarial fracture has perfect sensitivity (100%) for subsequent development of delayed epidural hematoma in our study population. Moreover, a contralateral calvarial fracture involving 2 or more bone plates had an especially high diagnostic odds ratio of 41 for delayed epidural hematoma. Recognition of skull fracture patterns associated with delayed epidural hematoma following decompressive craniectomy may reduce morbidity and mortality by prompting early postoperative intervention in high-risk situations.


Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay.
To measure the virus load in patients with symptomatic Epstein-Barr virus (EBV) infections, we used a real-time PCR assay to quantify the amount of EBV DNA in blood. The real-time PCR assay could detect from 2 to over 10(7) copies of EBV DNA with a wide linear range. We estimated the virus load in peripheral blood mononuclear cells (PBMNC) from patients with symptomatic EBV infections. The mean EBV-DNA copy number in the PBMNC was 10(3.7) copies/microg of DNA in patients with EBV-related lymphoproliferative disorders, 10(4.1) copies/microg of DNA in patients with chronic active EBV infections, and 10(2.2) copies/microg of DNA in patients with infectious mononucleosis. These numbers were significantly larger than those in either posttransplant patients or immunocompetent control patients without EBV-related diseases. In a patient with infectious mononucleosis, the virus load decreased as the symptoms resolved. The copy number of EBV DNA in PBMNC from symptomatic EBV infections was correlated with the EBV-positive cell number determined by the in situ hybridization assay (r = 0.842; P < 0.0001). These results indicate that the real-time PCR assay is useful for diagnosing symptomatic EBV infection and for monitoring the virus load.


Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis.
This is the first study aiming to determine the therapeutic effects of the Sambucus ebulus aquatic extract as an antileishmanial herbal drug and evaluate the immune responses in Leishmania major major infected BALB/c mice. The antileishmanial activity of S ebulus aquatic extract was evaluated using MTT test as well as parasite rescue and transformation assay. Footpad swelling and parasite load of infected mice were measured by several techniques. The immune responses were evaluated by measuring the levels of IFN-γ, IL-4, nitric oxide and arginase. The results indicated that S. ebulus can significantly decrease L. major promastigotes and amastigotes viability, but it was not toxic to macrophages. The lesion size, parasite burden and the level of ARG decreased in the treated infected mice, while the IFN-γ-to-IL-4 ratio and the level of NO increased significantly. Altogether, the S. ebulus extract is an effective compound for killing Leishmania parasite without excessive toxicity to the host cells and can cure the CL by switching the host immune responses towards Th1 response. Thus, it may be a perfect therapeutic option for CL treatment.


Targeting amyloid precursor protein secretases: Alzheimer's disease and beyond.
This review evaluates past and present clinical trials, as well as the current preclinical drug candidates focused on treating Alzheimer's disease (AD), in order to better assess the trends in AD drug discovery in context with specific drug mechanisms. The author begins by presenting a summary of the results of over 160 clinical trials targeted at AD, of which 52% have either failed to meet clinical endpoints or stalled (defined for the purpose of this review as no clinical or publicly mentioned progress for at least 3 years). The author postulates that many of the current clinical approaches fail to sufficiently regulate the amyloid cascade that includes, but is not limited to, the production of soluble β-amyloid precursor protein, β-amyloid and/or amyloid precursor protein intracellular domain and including activation of the tau cascade, ultimately translating to no improvement in cognitive function. To support this argument, the author compares clinical results and peer-reviewed opinions to postulate that appropriately focused multifunctional or dual pathway drugs could make the optimal candidate(s) for further investigations.


Porcine circovirus type 2 in muscle and bone marrow is infectious and transmissible to naïve pigs by oral consumption.
Pork products are a possible source of introduction of PCV2 isolates into a pig population. However, limited work has been done on the transmission through meat of porcine circovirus type 2 (PCV2), a virus associated with several disease syndromes in pigs. The objectives of this study were to determine if pork products from PCV2-infected pigs contain PCV2 DNA/antigen and to determine if the PCV2 present in the tissues is infectious by performing in vitro and in vivo studies. Skeletal muscle, bone marrow, and lymphoid tissues from pigs experimentally inoculated with PCV2 were collected 14 days post-inoculation (DPI). The tissues were tested for presence of PCV2 DNA by quantitative real-time PCR, for PCV2 antigen by immunohistochemistry (IHC), and for presence of infectious PCV2 by virus isolation and inoculation of PCV2 naïve pigs. Lymphoid tissues contained the highest amount of PCV2 (positive by PCR, IHC, and virus isolation), bone marrow contained a lower amount of PCV2 (positive by PCR and IHC but negative by virus isolation), and skeletal muscle contained the lowest amount of PCV2 (positive by PCR but negative by IHC and virus isolation). Naïve pigs fed for three consecutive days with either skeletal muscle, bone marrow, or lymphoid tissues all became PCV2 viremic as determined by quantitative real-time PCR on serum starting at 7 DPI. The pigs also seroconverted to PCV2 as determined by PCV2 IgM and IgG ELISA. In addition, PCV2 antigen was detected by IHC stains in lymphoid tissues and intestines collected from the majority of these pigs. Results from this study indicate that uncooked PCV2 DNA positive lymphoid tissues, bone marrow, and skeletal muscle from PCV2 viremic pigs contain sufficient amount of infectious PCV2 to infect naïve pigs by the oral route.


Prediction of Spheroid Cell Death Using Fluorescence Staining and Convolutional Neural Networks.
Three-dimensional (3D) cell culture is emerging for drug design and drug screening. Skin toxicity is one of the most important assays for determining the toxicity of a compound before being used in skin application. Much work has been done to find an alternative assay without animal experiments. 3D cell culture is one of the methods that provides clinically relevant models with superior clinical translation compared to that of 2D cell culture. In this study, we developed a spheroid toxicity assay using keratinocyte HaCaT cells with propidium iodide and calcein AM. We also applied the transfer learning-containing convolutional neural network (CNN) to further determine spheroid cell death with fluorescence labeling. Our result shows that the morphologies of the spheroid are the key features in determining the apoptosis cell death of the HaCaT spheroid. Our CNN model provided good statistical measurement in terms of accuracy, precision, and recall in both validation and external test data sets. One can predict keratinocyte spheroid cell death if that spheroid image contains the fluorescence signals from propidium iodide and calcein AM. The CNN model can be accessed in the web application at https://qsarlabs.com/#spheroiddeath.


A score-based method of immune status evaluation for healthy individuals with complete blood cell counts.
With the COVID-19 outbreak, an increasing number of individuals are concerned about their health, particularly their immune status. However, as of now, there is no available algorithm that effectively assesses the immune status of normal, healthy individuals. In response to this, a new score-based method is proposed that utilizes complete blood cell counts (CBC) to provide early warning of disease risks, such as COVID-19. First, data on immune-related CBC measurements from 16,715 healthy individuals were collected. Then, a three-platform model was developed to normalize the data, and a Gaussian mixture model was optimized with expectation maximization (EM-GMM) to cluster the immune status of healthy individuals. Based on the results, Random Forest (RF), Light Gradient Boosting Machine (LightGBM) and Extreme Gradient Boosting (XGBoost) were used to determine the correlation of each CBC index with the immune status. Consequently, a weighted sum model was constructed to calculate a continuous immunity score, enabling the evaluation of immune status. The results demonstrated a significant negative correlation between the immunity score and the age of healthy individuals, thereby validating the effectiveness of the proposed method. In addition, a nonlinear polynomial regression model was developed to depict this trend. By comparing an individual's immune status with the reference value corresponding to their age, their immune status can be evaluated. In summary, this study has established a novel model for evaluating the immune status of healthy individuals, providing a good approach for early detection of abnormal immune status in healthy individuals. It is helpful in early warning of the risk of infectious diseases and of significant importance.


Improving quality of experience in m-health monitoring system.
Quality of Experience (QoE) is proposed to evaluate user's overall satisfaction with the network system and services. For m-health systems, improving QoE means starting from user's view to make patients and doctors (the main users of m-health system who are especially captious to services related to health) to achieve best satisfaction. In this paper, we proposed an improved model for QoE of m-health systems based on energy consumption and information integrity received by the users, and then explore on how the users' satisfaction with m-health systems' energy consumption and received information integrity by exponential formula, which is influenced by the quantity of the transmitted information. Finally, from the results of simulation, we concluded that the appropriate compression of information quantity is the best way to improve QoE performance of the m-health system.


A longitudinal qualitative exploration of healthcare and informal support needs among survivors of critical illness: the RELINQUISH protocol.
Survival following critical illness is associated with a significant burden of physical, emotional and psychosocial morbidity. Recovery can be protracted and incomplete, with important and sustained effects upon everyday life, including family life, social participation and return to work. In stark contrast with other critically ill patient groups (eg, those following cardiothoracic surgery), there are comparatively few interventional studies of rehabilitation among the general intensive care unit patient population. This paper outlines the protocol for a sub study of the RECOVER study: a randomised controlled trial evaluating a complex intervention of enhanced ward-based rehabilitation for patients following discharge from intensive care. The RELINQUISH study is a nested longitudinal, qualitative study of family support and perceived healthcare needs among RECOVER participants at key stages of the recovery process and at up to 1 year following hospital discharge. Its central premise is that recovery is a dynamic process wherein patients' needs evolve over time. RELINQUISH is novel in that we will incorporate two parallel strategies into our data analysis: (1) a pragmatic health services-oriented approach, using an a priori analytical construct, the 'Timing it Right' framework and (2) a constructivist grounded theory approach which allows the emergence of new themes and theoretical understandings from the data. We will subsequently use Qualitative Health Needs Assessment methodology to inform the development of timely and responsive healthcare interventions throughout the recovery process. The protocol has been approved by the Lothian Research Ethics Committee (protocol number HSRU011). The study has been added to the UK Clinical Research Network Database (study ID. 9986). The authors will disseminate the findings in peer reviewed publications and to relevant critical care stakeholder groups.


Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement Metathesis.
Herein, a facile synthesis of intricate fused N-heterocycles is disclosed by employing C-H activation and ring-rearrangement metathesis/enyne ring-rearrangement metathesis as key steps. Interestingly, some of these N-heterocyclic products possess the tricyclic core of epimeloscine, deoxycalyciphylline B, daphlongamine H, isodaphlongamine H, and a bioactive alkaloid, annotinolide A, which shows antiaggregation activity against amyloid-β (Aβ)1-42 peptide aggregation. Moreover, various starting materials required in this protocol are easily assembled via C-X bond annulation of 2-bromo-N-protected aniline with norbornadiene or directing group-assisted ruthenium-catalyzed C-H activation of N-methoxybenzamide.


Helicobacter pylori infection is a major risk factor for gastric carcinoma in young patients.
Helicobacter pylori has been established as a risk factor for gastric carcinoma (GCa). Since before the discovery of H. pylori, atrophic gastritis and intestinal metaplasia have been linked to GCa, especially the intestinal-type tumor. The prevalence of H. pylori infection and atrophic gastritis increase with age. Thus, analysis of H. pylori infection in young patients with GCa could help clarify the role of this bacterium in the development of GCa. Accordingly, we investigated the relationship between H. pylori infection, GCa, and histologic gastritis in patients less than 30 years old. Fifty GCa patients less than 30 years (mean, 26.4 years) and 100 sex- and age-matched controls (mean, 26.8 years) were examined for the presence of H. pylori infection and histologic gastritis. The prevalence of H. pylori infection was significantly higher in GCa patients than in controls (94% versus 40%, P < 0.01). Its prevalence was not associated with tumor location, tumor stage, or histologic type. Gastritis, atrophy, and intestinal metaplasia significantly increased the risk of GCa. By means of multiple logistic regression analysis, the odds ratio for the risk of GCa in H. pylori-positive subjects was found to be 23.5 (95% confidence interval, 6.84-80.7). We confirmed a strong association between H. pylori infection and GCa in young patients. Along with H. pylori infection, histologic gastritis might play an important role in the pathogenesis of GCa in these patients.


Prevalence of anti-peptidylarginine deiminase type 4 antibodies in rheumatoid arthritis and unaffected first-degree relatives in indigenous North American Populations.
To determine whether anti-peptidylarginine deiminase type 4 (PAD4) antibodies were present in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA) in 2 indigenous North American populations with high prevalence of RA. Participants were recruited from 2 indigenous populations in Canada and the United States, including patients with RA (probands), their unaffected FDR, and healthy unrelated controls. Sera were tested for the presence of anti-PAD4 antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF). HLA-DRB1 subtyping was performed and participants were classified according to number of shared-epitope alleles present. Antibodies to PAD4 were detected in 24 of 82 (29.3%) probands; 2 of 147 (1.4%) relatives; and no controls (p < 0.0001). Anti-CCP was present in 39/144 (27.1%) of the relatives, and there was no overlap between positivity for anti-CCP and PAD4 in the relatives. In RA patients, anti-PAD4 antibodies were associated with disease duration (p = 0.0082) and anti-CCP antibodies (p = 0.008), but not smoking or shared-epitope alleles. Despite a significant prevalence of anti-CCP in FDR, anti-PAD4 antibodies were almost exclusively found in established RA. The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration and anti-CCP in RA.


Myeloperoxidase-catalyzed metabolism of etoposide to its quinone and glutathione adduct forms in HL60 cells.
Etoposide is a widely used antineoplastic agent that has provided great success in the treatment of childhood leukemias and other malignancies. Unfortunately, its use is associated with the increased risk of development of secondary acute myelogenous leukemias involving translocations at the MLL gene in chromosome band 11q23. Previous studies showed that the phenoxyl radical of etoposide can be generated by myeloperoxidase (MPO), an enzyme prevalent in myeloid progenitor cells that can derive myelogenous leukemias. Disproportionation of this radical leads to formation of the redox active etoposide ortho-quinone metabolite. We hypothesized that etoposide ortho-quinone could therefore form in myeloid progenitor cells and might be a contributor to the development of treatment-related secondary leukemias. Etoposide ortho-quinone is an inherently unstable compound and readily reacts with glutathione in aqueous media without any requirement for catalytic assistance from glutathione S-transferase. We looked for the presence of its glutathione adduct as an indicator of etoposide ortho-quinone in cells. MPO-expressing human myeloid leukemia HL60 cells were treated with etoposide for 0.5 h in the presence and absence of the cosubstrate of MPO, hydrogen peroxide. Cell lysates and medium were analyzed by LC-ESI-ion trap-MS and MS/MS, which yielded clear evidence of the intracellular formation of the etoposide ortho-quinone-glutathione adduct. A stable isotope-labeled form of the GSH adduct was synthesized and employed as an isotope dilution internal standard in LC-ESI-quadrupole-MS analyses. The glutathione adduct level was dependent on the concentration of etoposide added to the cells. More importantly, the formation of the glutathione adduct was significantly suppressed by the pretreatment of HL60 cells with the heme synthesis inhibitor succinylacetone (p < 0.001), which resulted in a decreased level and activity of MPO. These results are consistent with the idea that MPO is responsible for the conversion of etoposide to its ortho-quinone in these cells.


Risk of Neutropenia-Related Hospitalization in Patients Who Received Colony-Stimulating Factors With Chemotherapy for Breast Cancer.
Purpose To describe outcomes after granulocyte colony-stimulating factor (G-CSF) prophylaxis in patients with breast cancer who received chemotherapy regimens with low-to-intermediate risk of induction of neutropenia-related hospitalization. Patients and Methods We identified 8,745 patients age ≥ 18 years from a medical and pharmacy claims database for 14 commercial US health plans. This retrospective analysis included patients with breast cancer who began first-cycle chemotherapy from 2008 to 2013 using docetaxel and cyclophosphamide (TC); docetaxel, carboplatin, and trastuzumab (TCH); or doxorubicin and cyclophosphamide (conventional-dose AC) regimens. Primary prophylaxis (PP) was defined as G-CSF administration within 5 days of beginning chemotherapy. Outcome was neutropenia, fever, or infection-related hospitalization within 21 days of initiating chemotherapy. Multivariable regressions and number-needed-to-treat analyses were used. Results A total of 4,815 patients received TC (2,849 PP; 1,966 no PP); 2,292 patients received TCH (1,444 PP; 848 no PP); and 1,638 patients received AC (857 PP; 781 no PP) regimen. PP was associated with reduced risk of neutropenia-related hospitalization for TC (2.0% PP; 7.1% no PP; adjusted odds ratio [AOR], 0.29; 95% CI, 0.22 to 0.39) and TCH (1.3% PP; 7.1% no PP; AOR, 0.19; 95% CI, 0.12 to 0.30), but not AC (4.7% PP; 3.8% no PP; AOR, 1.21; 95% CI, 0.75 to 1.93) regimens. For the TC regimen, 20 patients (95% CI, 16 to 26) would have to be treated for 21 days to avoid one neutropenia-related hospitalization; with the TCH regimen, 18 patients (95% CI, 13 to 25) would have to be treated. Conclusion Primary G-CSF prophylaxis was associated with low-to-modest benefit in lowering neutropenia-related hospitalization in patients with breast cancer who received TC and TCH regimens. Further evaluation is needed to better understand which patients benefit most from G-CSF prophylaxis in this setting.


The pathologic implications of vibration disease.
Vibration disease is a syndrome comprising a multitude of symptoms with ensuing pathologic alterations to the vasculature, nerves, and musculoskeletal system. There are various theories regarding the contributing factors involved in the etiology and pathogenesis of this disorder. This article reviews the pertinent theories and details the major aspects of vibration disease. It also introduces the potential synergistic role that the various affected systems have in influencing each other throughout the progression of this syndrome.


ZnO-based nanocarriers for drug delivery application: From passive to smart strategies.
Due to the excellent biocompatibility as well as the low cost, nanoscale ZnO shows a great potential in drug delivery application. The richness of the structures, easy modification and pleasant properties of nanoscale ZnO make these materials reasonable choices for drug delivery. In the recent decade, various ZnO nanostructures as well as nanohybrids have been carried out for optimizational drug loading and carrying. To control the drug release behavior, many nanoscale ZnO-based smart drug delivery systems which are responsive to particular stimuli via characteristics of ZnO (e.g. dissolution in acid, microwave absorbing, hydrophobic/hydrophilic transition) have been successfully synthesized. Herein, we review the recent exciting progress on the nanoscale ZnO-based drug delivery systems: from the passive to smart strategies.


Tai Chi Combined With Resistance Training for Adults Aged 50 Years and Older: A Systematic Review.
Despite Tai Chi and resistance training being recommended as suitable exercise for older adults, there are no systematic reviews synthesizing the effectiveness of a combination of Tai Chi and resistance training on health promotion of older adults. This study aimed to review the existing literature regarding the effect of Tai Chi and resistance training on physical health, mental health, pain, health-related quality of life, and age-related impairment in adults aged 50 years and older. A systematic review was conducted to report the health outcomes of Tai Chi combined with resistance training research in adults aged 50 years and older. Articles were identified by searching PubMed, Scopus, Web of Science, CINAHL, MEDLINE, Physiotherapy Evidence Database (PEDro), and the Cochrane library using search terms representing "Tai Chi" and "resistance" and "older adults." Quantitative experimental studies with participants aged 50 years and older, where one of the interventions was Tai Chi and resistance training, were included. The literature search yielded 648 articles from which 7 met the inclusion criteria. Collectively, the studies involved 703 participants aged 50 years and older, including healthy older adults, older adults with history of falls, postmenopausal women, and people diagnosed with end-stage hip osteoarthritis. Studies included different Tai Chi forms in combination with various types of resistance training. Training sessions were 2 to 7.5 h/wk and lasted between 12 weeks and 12 months. After long-term Tai Chi and resistance training, the participants showed significant improvement in upper and lower extremity muscle strength, aerobic endurance, balance, and mobility. However, 1 study failed to show improvement in Functional Movement Screening compared with traditional Tai Chi and nonexercise groups. No study examined the effects of Tai Chi and resistance training on health-related quality of life, fear of falling, or mental health in adults aged 50 years and older. The review supports that Tai Chi in combination with resistance training improves physical function and muscle strength in adults aged 50 years and older.


Exploring a prototype for cooperative structural phase transition in cobalt(II) spin crossover compounds.
The creation of magnetically switchable materials that concurrently incorporate spin crossover (SCO) and a structural phase transition (SPT) presents a significant challenge in materials science. In this study, we prepared four structurally related cobalt(II)-based SCO compounds: two one-dimensional (1D) chains of {[(enbzp)Co(μ-L)](ClO4)2·sol}n (L = bpee, sol = 2MeOH·H2O, 1; L = bpea, sol = none, 2; enbzp = N,N'-(ethane-1,2-diyl)bis(1-phenyl-1-(pyridin-2-yl)methanimine); bpee = 1,2-bis(4-pyridyl)ethylene; and bpea = 1,2-bis(4-pyridyl)ethane) and their discrete segments, [{(enbzp)Co}2(μ-L)](ClO4)4·2MeOH (L = bpee, 3; L = bpea, 4). In all of these complexes, each Co(II) center is equatorially chelated by the planar tetradentate ligand enbzp and connected to a chain or dinuclear structure through bpee or bpea ligands along its axial direction. All of the complexes, including their desolvated phases, displayed overall incomplete and gradual SCO properties. Interestingly, the desolvated phase of 1 exhibited an additional non-spin magnetic transition characterized by wide room-temperature hysteresis (>40 K), which was reversible and rate-dependent, showcasing the synergy between SCO and SPT manifested through slow kinetics. We discuss the possible reasons for the distinct features and our findings demonstrate that the combination of a rigid polymeric framework with flexible substituents holds promise for achieving synergy between SCO and SPT.


Expression of the major gas vesicle protein gene in the halophilic archaebacterium Haloferax mediterranei is modulated by salt.
In the moderately to extremely halophilic archaebacterium Haloferax mediterranei gas vacuoles are not observed before the stationary phase of growth, and only when the cells are grown in media containing more than 17% total salt. Under the electron microscope, isolated gas vesicles appear as cylindrical structures with conical ends that reach a maximal length of 1.5 microns; this morphology is different from the spindle-shaped gas vesicles found in the Halobacterium halobium wild type which expresses the plasmid-borne p-vac gene, but resembles that of gas vesicles isolated from H. halobium strains expressing the chromosomal c-vac gene. Both the p-vac and the c-vac genes encode very similar structural proteins accounting for the major part of the "membrane" of the respective gas vesicles. The homologous mc-vac gene was isolated from Hf. mediterranei using the p-vac gene as probe. The mc-vac coding region indicates numerous nucleotide differences compared to the p-vac anc c-vac genes; the encoded protein is, however, almost identical to the c-vac gene product. The start point of the 310 nucleotide mc-vac transcript determined by primer extension analysis and S1 mapping was located 20 bp upstream of the ATG start codon, which is at the same relative position as found for the other two vac mRNAs. During the growth cycle, mc-vac mRNA was detectable in Hf. mediterranei cells grown in 15% as well as 25% total salt, with a maximal level in the early stationary phase of growth. The relative abundance of mc-vac mRNA in cells grown at 25% salt was sevenfold higher than in cells grown in 15% total salt.