Geminiviral V2 Protein Suppresses Transcriptional Gene Silencing through Interaction with AGO4.
In plants, RNA-directed DNA methylation (RdDM)-mediated transcriptional gene silencing (TGS) is a natural antiviral defense against geminiviruses. Several geminiviral proteins have been shown to target the enzymes related to the methyl cycle or histone modification; however, it remains largely unknown whether and by which mechanism geminiviruses directly inhibit RdDM-mediated TGS. In this study, we showed that Cotton leaf curl Multan virus (CLCuMuV) V2 directly interacts with Nicotiana benthamiana AGO4 (NbAGO4) and that the L76S mutation in V2 (V2L76S) abolishes such interaction. We further showed that V2, but not V2L76S, can suppresses RdDM and TGS. Silencing of NbAGO4 inhibits TGS, reduces the viral methylation level, and enhances CLCuMuV DNA accumulation. In contrast, the V2L76S substitution mutant attenuates CLCuMuV infection and enhances the viral methylation level. These findings reveal that CLCuMuV V2 contributes to viral infection by interaction with NbAGO4 to suppress RdDM-mediated TGS in plants.IMPORTANCE In plants, the RNA-directed DNA methylation (RdDM) pathway is a natural antiviral defense mechanism against geminiviruses. However, how geminiviruses counter RdDM-mediated defense is largely unknown. Our findings reveal that Cotton leaf curl Multan virus V2 contributes to viral infection by interaction with NbAGO4 to suppress RNA-directed DNA methylation-mediated transcriptional gene silencing in plants. Our work provides the first evidence that a geminiviral protein is able to directly target core RdDM components to counter RdDM-mediated TGS antiviral defense in plants, which extends our current understanding of viral counters to host antiviral defense.


Using multi-class queuing network to solve performance models of e-business sites.
Due to e-business's variety of customers with different navigational patterns and demands, multi-class queuing network is a natural performance model for it. The open multi-class queuing network(QN) models are based on the assumption that no service center is saturated as a result of the combined loads of all the classes. Several formulas are used to calculate performance measures, including throughput, residence time, queue length, response time and the average number of requests. The solution technique of closed multi-class QN models is an approximate mean value analysis algorithm (MVA) based on three key equations, because the exact algorithm needs huge time and space requirement. As mixed multi-class QN models, include some open and some closed classes, the open classes should be eliminated to create a closed multi-class QN so that the closed model algorithm can be applied. Some corresponding examples are given to show how to apply the algorithms mentioned in this article. These examples indicate that multi-class QN is a reasonably accurate model of e-business and can be solved efficiently.


Understanding interleukin 11 as a disease gene and therapeutic target.
Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.


A cineradiographic and electromyographic study of mastication in Tenrec ecaudatus.
Regular chewing was studied in the specialized Malagasy insectivore Tenrec ecaudatus with the aid of precisely correlated electromyography of the main adductors, digastrics, and two hyoid muscles and cineradiography for which metallic markers were placed in the mandibles, tongue, and hyoid bone. During the power stroke the body of the mandible moves dorsally and medially. The medially directed component of movement at this time is greatly increased by simultaneous rotation of the mandible about its longitudinal axis. The highly mobile symphysis, spherical dentary condyle, loss of superficial masseter muscle and zygoma, and the simplified zalamnodont molars all appear to be related to the large amount of mandibular rotation that occurs during occlusion. The balancing side lateral pterygoid muscle (inferior head) apparently shifts the working side mandible laterally during the last part of opening and the first part of closing. The working side temporalis and the superficial masseter muscle are both responsible for the shift back to the midline. The temporalis is usually active to the same extent on the working and balancing sides during the power stroke. The level of activity (amplitude) of the temporalis and duration of the power stroke increase with harder foods. Whenever soft foods are chewed, the superficial masseter is only active on the working side; whenever foods of increasing hardness are chewed, its level of activity on the balancing side increases to approach that of the working side. Mandibular rotation is greatly reduced when hard foods are chewed.


Estrogen and androgen regulate actin-remodeling and endocytosis-related genes during rat spermiation.
Spermiation, the sperm release process, is imperative to male fertility and reproduction. Morphologically, it is characterized by removal of atypical adherens junctions called ectoplasmic specializations, and formation of transient endocytic devices called tubulobulbar complexes requiring cytoskeleton remodeling and recruitment of proteins needed for endocytosis. Earlier, estrogen administration to adult male rats was seen to cause spermiation failure due to disruption of tubulobulbar complexes. This was accompanied by reduction in intratesticular testosterone levels and increase in intratesticular estrogen along with deregulation of genes involved in cytoskeleton remodeling (Arpc1b, Evl and Capg) and endocytosis (Picalm, Eea1 and Stx5a). In the present study, we aim to understand the role of estrogen and androgen in regulating these genes independently using seminiferous tubule culture system treated with estrogen, androgen or agonists and antagonists of estrogen receptors. We find that transcripts of Arpc1b, Evl and Picalm are responsive to estrogen while those of Picalm, Eea1 and Stx5a are responsive to androgen. We also find that the estrogen regulation of Arpc1b and Evl is mediated through estrogen receptor β and that of Picalm occurs through estrogen receptors α and β. Localization of these proteins at or in the vicinity of tubulobulbar complexes reveals that ARPC1B, EVL, PICALM, EEA1 and STX5A seem to be involved in spermiation. Thus, estrogen and androgen regulate specific genes in seminiferous tubules that could play a role in spermiation.


Use of subjective global assessment and clinical outcomes in critically ill geriatric patients receiving nutrition support.
The objective of this study is to examine the prevalence of malnutrition and evaluate the nutrition status and clinical outcome in hospitalized patients aged 65 years and older receiving enteral-parenteral nutrition. This retrospective study was carried out at Başkent University Hospital, Adana, Turkey. A total of 119 patients older than 65 years were recruited. Patients were classified into 3 groups: protein-energy malnutrition (PEM), moderate PEM, and well nourished according to subjective global assessment (SGA) at admission. All patients were fed by enteral or parenteral route. Acute physiological and chronic health evaluation (APACHE-2) and simplified acute physiology (SAPS 2) scores were recorded in patients followed in the intensive care unit (ICU). Nutrition status was assessed with biochemical (serum albumin, serum prealbumin) parameters. These results were compared with mortality rate and length of hospital stay (LOS). The subjects' mean (+/-SD) age was 73.1 +/- 5.4 years. Using SGA, 5.9% (n = 7) of the patients were classified as severely PEM, 27.7% (n = 33) were classified as moderately PEM, and 66.4% (n = 79) were classified as well nourished. Some 73.1% (n = 87) of the patients were followed in the ICU. Among all patients, 42.9% (n = 51) were fed by a combined enteral-parenteral route, 31.1% (n = 37) by an enteral route, 18.5% (n = 22) by a parenteral route, and 7.6% (n = 9) by an oral route. The average length of stay for the patients was 18.9 +/- 13.7 days. The mortality rate was 44.5% (n = 53). The mortality rate was 43% (n = 34) in well-nourished patients (n = 79), 48.5% (n = 16) in moderately PEM patients (n = 33), and 42.9% (n = 3) in severely PEM patients (n = 7) (P = .86). The authors observed no difference between well-nourished and malnourished patients with regard to the serum protein values on admission, LOS, and mortality rate. In this study, malnutrition as defined by SGA did not influence the mortality rate of critically ill geriatric patients receiving enteral or parenteral nutrition. Furthermore, no factor was found to be a good predictor of survival.


Lung Adenocarcinoma Harboring EGFR Kinase Domain Duplication (EGFR-KDD) Confers Sensitivity to Osimertinib and Nivolumab: A Case Report.
Kinase domain duplication of EGFR (EGFR-KDD) is a rare oncogenic driver alteration and serves as a potential therapeutic target. Its effect on EGFR-tyrosine kinase inhibitors (TKIs), especially the third-generation drug Osimertinib, and immune checkpoint inhibitors (ICIs) remains inconclusive. A 45-year old male with lung adenocarcinoma progressed with liver metastasis after receiving pemetrexed and cisplatin as adjuvant chemotherapy. Targeted next-generation sequencing (NGS) identified an EGFR-KDD in the resected left upper lung. Icotinib was used in the following treatment and the liver metastasis was found to shrink but the progression-free survival (PFS) only lasted for 4 months with the appearance of right hepatic metastasis. Meantime, the same EGFR-KDD was identified in the left hepatic re-biopsy. Afterward, the patient benefited from the third-line therapy of Osimertinib with a PFS as long as 21 months. Then he progressed with enlarged mediastinal lymph nodes, and targeted NGS consistently identified EGFR-KDD, as well as a new RELN p.G1774E mutation. Given the continually increasing tumor mutation burden (TMB, 3.4 mutation/Mb) and PD-L1 expression-based tumor proportion score (TPS, 1%), Nivolumab was used as the fourth-line salvage therapy, which lead to considerable efficacy, with decreased blood carcinoembryonic antigen (CEA), regressed mediastinal lymph nodes, and reduced liver metastases. Our case provided direct evidence to support the role of Osimertinib in the treatment of EGFR-KDD, as well as added valuable insights into application of immune-based therapeutics in the specific subgroups bearing EGFR alteration(s).


The Sudden Savant: A New Form of Extraordinary Abilities.
Savant Syndrome previously has been characterized as either congenital or acquired. This report describes sudden savant syndrome in which neurotypical persons have the sudden emergence of savant skills without underlying disability or brain injury and without prior interest or ability in the newly emerged skill areas. Eleven cases are described in which savant abilities suddenly and unexpectedly surfaced in neurotypical persons with no special prior interest or ability in the new skills, accompanied by an obsessive interest with and compulsive need to display the new abilities. All participants completed an online survey to record their demographics and skill characteristics. The acquired savant, and now the sudden savant, raise questions about the dormant potential for such buried skills in everyone. The challenge is to be able to tap such latent abilities without head injury or other precipitating events. This paper documents 11 cases of sudden savant syndrome, which is a new and additional form of savant abilities surfacing in neurotypical persons without developmental disabilities (such as autism) or head or other brain injury (acquired savant syndrome). It opens new paths of inquiry for exploration of extraordinary abilities perhaps within everyone.


Exposure to particulate air pollution and risk of deep vein thrombosis.
Particulate air pollution has been linked to heart disease and stroke, possibly resulting from enhanced coagulation and arterial thrombosis. Whether particulate air pollution exposure is related to venous thrombosis is unknown. We examined the association of exposure to particulate matter of less than 10 microm in aerodynamic diameter (PM10) with deep vein thrombosis (DVT) risk in 870 patients and 1210 controls from the Lombardy region in Italy, who were examined between 1995 and 2005. We estimated exposure to PM10 in the year before DVT diagnosis (cases) or examination (controls) through area-specific mean levels obtained from ambient monitors. Higher mean PM10 level in the year before the examination was associated with shortened prothrombin time (PT) in DVT cases (standardized regression coefficient [beta] = -0.12; 95% confidence interval [CI], -0.23 to 0.00) (P = .04) and controls (beta = -0.06; 95% CI, -0.11 to 0.00) (P = .04). Each increase of 10 microg/m3 in PM10 was associated with a 70% increase in DVT risk (odds ratio [OR], 1.70; 95% CI, 1.30 to 2.23) (P < .001) in models adjusting for clinical and environmental covariates. The exposure-response relationship was approximately linear over the observed PM10 range. The association between PM10 level and DVT risk was weaker in women (OR, 1.40; 95% CI, 1.02 to 1.92) (P = .02 for the interaction between PM10 and sex), particularly in those using oral contraceptives or hormone therapy (OR, 0.97; 95% CI, 0.58 to 1.61) (P = .048 for the interaction between PM10 level and hormone use). Long-term exposure to particulate air pollution is associated with altered coagulation function and DVT risk. Other risk factors for DVT may modulate the effect of particulate air pollution.


Optimization of radiative heat transfer in hyperbolic metamaterials for thermophotovoltaic applications.
Using our recently developed method we analyze the radiative heat transfer in micron-thick multilayer stacks of metamaterials with hyperbolic dispersion. The metamaterials are especially designed for prospective thermophotovoltaic systems. We show that the huge transfer of near-infrared thermal radiation across micron layers of metamaterials is achievable and can be optimized. We suggest an approach to the optimal design of such metamaterials taking into account high temperatures of the emitting medium and the heating of the photovoltaic medium by the low-frequency part of the radiation spectrum. We show that both huge values and frequency selectivity are achievable for the radiative heat transfer in hyperbolic multilayer stacks.


The application of economics in animal health programmes: a practical guide.
Economic analysis is a valuable technique in the planning and management of animal health programmes at the national policy level and at the level of individual livestock enterprises. Considerable experience has now been accumulated in the adaptation of methods of economics to address decisions on disease control issues. Different methods are appropriate for endemic diseases, for diseases which occur intermittently as local outbreaks, and for diseases which have the potential to cause an epidemic. A guide to the selection of the most suitable method is provided. The information required for analysis at individual herd level is much simpler than that required for national policy decisions and funding decisions by international agencies; an outline of the requirements for each level of analysis is provided. Issues surrounding the degree of risk of different choices are examined, and the application of decision analysis to higher-risk choices is introduced. Ways in which difficulties and hazards can be overcome are suggested for those unfamiliar with the techniques. Finally, procedures to provide confidence in the results of evaluations through sensitivity analysis are explained.


Online Ratings of Spine Surgeons: Analysis of 208 Surgeons.
Observational study. To evaluate the online ratings of spine surgeons and variables that may affect online ratings. Physician review Web sites (PRW) are rapidly growing for-profit businesses. Most orthopedic surgeons are rated on at least one PRW as are other surgical specialists. To date the online ratings of spine surgeons have not been evaluated. Cervical Spine Research Society surgeon ratings on five physician rating Web sites were performed in April 2016: "healthgrade.com," "vitals.com," "ratemd.com," "webmd.com," and "yelp.com." Numeric ratings from the PRWs were standardized on a scale of 0 to 100 with a higher score indicating positive ratings. Sex, practice sector (academic or private), specialty (orthopedics or neurosurgery), geographic location, and years of practice were also collected. A total of 209 spine surgeons were included in our study. Of the 209 spine surgeons, 208 (99.52%) were rated at least once in one of the five PRWs. Average number of ratings per surgeon was 2.96. Average rating was 80 (40-100). There were four female (1.92%) and 204 male surgeons (98.1%). There were 121 (58.2%) in academic practice and 87 (41.8%) in private practice. There were 175 (84.1%) orthopedic surgeons and 33 (15.9%) neurosurgeons. Most of the surgeons were Caucasian 163 (78.4%) and worked in the South and Northeast 135 (64.9%). Those in academic practice had significantly higher ratings (81.6 vs. 77.65; P = 0.026). Number of years in practice was significantly associated with ratings (P = 0.0003) with those in practice for 21 or more years having significantly lower ratings. In this first study evaluating the online ratings of spine surgeons, we found that 99.5% of spine surgeon had at least one rating on a PRW. The average score, 80, indicated mostly positive ratings. Being in practice for 20 years or less and being in academic practice significantly associated with higher ratings. 4.


Current challenges in antihypertensive treatment in the elderly.
Arterial hypertension affects more than 25% of the global population, and its prevalence is increasing with age. Arterial stiffening occurs with aging and results in a pattern of increased systolic and decreased diastolic blood pressure (BP). In the elderly population, elevated BP has been related with increased cardiovascular risk. Trials on this population have shown great benefits for morbidity and mortality from reducing systolic BP (SBP) levels to less than 150 mmHg. Most guidelines for the management of elderly hypertensive patients agree on BP reduction to less than 150/90 mmHg. However, there is still uncertainty whether further BP reduction could provide beneficial results. The recently published SPRINT trial demonstrated that reducing SBP to between 120 and 125 mmHg in patients over the age of 75 years is related with increased survival and is expected to affect future recommendations. On the contrary, the limited data that are available for octogenarians and frail nursing home patients create concerns for more aggressive BP strategies in these subgroups, and thus they should be treated more conservatively. Among the various antihypertensive classes of drugs, diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers were proved beneficial in the elderly and are favored as first choices for the management of elderly hypertensive individuals. Given the common coexistence of other comorbidities and polypharmacy, physicians should be careful when initiating or uptitrating treatments to avoid potential adverse events or interaction with other drugs or diseases.


High Expression of Human AugminComplex Submit 3 Indicates Poor Prognosis and Associates with Tumor Progression in Hepatocellular Carcinoma.
The function of human augmin complex unit 3(Haus3), a component of the HAU augmin-like complex, in various cancers is not clear. This study aims to elucidate the clinical significance and the role of Haus3 in tumor progression of hepatocellular carcinoma (HCC). We analyzed the expression of Haus3 in 50 HCC patients from The Cancer Genome Atlas and 137 HCC patients in our hospital. Compared with adjacent normal tissue, Haus3 expression assessed by immunohistochemical staining was dramatically increased in tumor tissues. A high level of Haus3 expression was significantly correlated with large tumor size (p=0.025) and tumor multiplicity (p=0.004). Univariate and multivariate survival analysis showed thatexpression of Haus3 was an independent prognostic factor for overall survival ofHCCpatients. Western blot analysis showed that Haus3 regulated the phosphorylation of PLK1-T210 and activity of the Cdk1/cyclin B1 complex, indicating that Haus3 disrupted G2/M phase arrest. In immunofluorescence studies, expression of Haus3 correlated with the level ofα-tubulin and γ-tubulin. In summary, Haus3 plays a vital role in regulatingtheactivityof PLK2-T210 and Cdk1/cyclin B1 complex in G2/M phasetransition and the expression of tubulins to ensure normal mitotic progression. Our data suggest that Haus3 might be a promising prognostic biomarker and molecular target of HCC.


Anti-argonaute2 (Ago2/Su) and -Ro antibodies identified by immunoprecipitation in primary anti-phospholipid syndrome (PAPS).
Primary anti-phospholipid syndrome (PAPS) is an autoimmune condition defined by anti-phospholipid antibodies (aPL) and thrombotic or obstetric events. Some PAPS can evolve into systemic lupus erythematosus (SLE) during follow-up. Few studies systematically examined lupus autoantibodies and their clinical significance in PAPS. The aim of our study is to analyze the clinical and laboratory correlations with lupus-related autoantibodies, detected by immunoprecipitation (IP), a technique not yet systematically applied to investigate autoantibodies in this condition. Sera from 52 PAPS patients were screened by indirect immunofluorescence (IIF) antinuclear antibodies (ANA), IP of ³⁵S-labeled K562 cell extract, and ELISA [anti-Argonaute2 (Ago2, Su), 60kRo, 52kRo, La, dsDNA)]. Anti-Ago2/Su positive sera were also tested for anti-GW bodies (GWBs) by IIF double staining, using rabbit anti-Rck/p54 serum. First, 56% of PAPS patients (29/52) were ANA positive, mainly with speckled pattern. Anti-Ago2/Su antibodies were found in 13% (7/52), anti-Ro/SSA in 10% (5/52), anti-La in one case. The clinical profile of patients did not seem to be related to the presence of these antibody specificities. However, levels of IgG anti-β2 glycoprotein I antibodies were lower in anti-Ago2/Su positive patients (p = 0.02). None of anti-Ago2/Su or -Ro patients developed SLE during a 2-year follow-up. Ago2 is a key component of GWBs, however, only 1/7 anti-Ago2/Su serum showed a typical cytoplasmic GWBs staining. Anti-Ago2/Su and -Ro antibodies are the two autoantibodies detected by IP in our PAPS cohort. Clarifying why Ago2/Su and Ro are specific targets of autoimmunity may help to understand the mechanisms of autoantibody production.


High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC.
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive. We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10-5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort. SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs.


MicroRNA-34c targets TGFB-induced factor homeobox 2, represses cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma.
MicroRNAs (miRs) are short, non-coding RNAs with post-transcriptional regulatory functions. Previous studies have demonstrated that miR-34c is involved in diverse biological processes, including carcinogenesis. The aim of the present study was to investigate the role of miR-34c and its target genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Expression levels of miR-34c and its predicted target genes were measured. The target genes were validated by a luciferase assay. The effects of miR-34c restoration were evaluated by the detection of HBV antigens, cell proliferation and apoptosis in vitro, in addition to the tumor growth in vivo. The data demonstrated that miR-34c was downregulated in HBV-associated HCC clinical tissues and HCC cell lines compared with their corresponding controls. transforming growth factor-β-induced factor homeobox 2 (TGIF2), a transcription factor repressing transforming growth factor-β (TGFβ) signaling, was observed to be upregulated and was identified as a target gene of miR-34c. The restoration of miR-34c in HepG2.2.15 cells suppressed TGIF2 expression, HBV replication and viral antigen synthesis; inhibited cell proliferation; and induced apoptosis. miR-34c also inhibited tumor growth in a mouse model. The present study indicates that miR-34c may act as a tumor suppressor by targeting TGIF2 during HBV-associated hepatocellular carcinogenesis. miR-34c and TGIF2 may represent key regulatory factors, diagnostic markers and therapeutic targets for the prevention and treatment of HBV-associated HCC.


[CT quantification of pleuropulmonary lesions in severe thoracic trauma].
Computed quantification of the extent of pleuropulmonary trauma by CT and comparison with conventional chest x-ray--Impact on therapy and correlation with mechanical ventilation support and clinical outcome. In a prospective trial, 50 patients with clinically suspicious blunt chest trauma were evaluated using CT and conventional chest x-ray. The computed quantification of ventilated lung provided by CT volumetry was correlated with the consecutive artificial respiration parameters and the clinical outcome. We found a high correlation between CT volumetry and artificial ventilation concerning maximal pressures and inspiratory oxygen concentration (FiO2, Goris-Score) (r = 0.89, Pearson). The graduation of thoracic trauma correlated highly with the duration of mechanical ventilation (r = 0.98, Pearson). Especially with regard to atelectases and lung contusions CT is superior compared to conventional chest x-ray; only 32% and 43%, respectively, were identified by conventional chest x-ray. CT allows rapid classification and quantification of pulmonary lesions after thoracic trauma and provides higher sensitivity and reliability. Because of the great correlation with the extent of artificial respiration in respect of duration and pressure, prognosis of the individual patient, as well as a differential therapy, appear possible.


Evidence-based postoperative pain management in nursing: is a randomized-controlled trial the most appropriate design?
There is an increasing drive to make nursing care evidence-based. High quality evidence from systematic reviews relevant to postoperative pain relief exists, yet pain after surgery remains poorly controlled for many patients. This study aimed to assess whether implementing evidence-based pain management improved postoperative pain outcomes. Pain on a 0-10 scale was the primary outcome and analgesic consumption a secondary outcome. A baseline audit was undertaken on four surgical wards to establish whether there was a need for the study. A randomized-controlled trial was then designed to assess the effects of implementing an evidence-based approach to postoperative pain management. The four wards were randomized to receive the intervention or act as a control. Outcomes were assessed 3 months after the intervention on both intervention and control wards. The intervention (implementation of an oral analgesic algorithm derived from systematic reviews) was then implemented on the control wards and outcomes reassessed after 3 months on the control wards. The intervention was designed using an evidence-based approach to effective implementation. Four interactive sessions covered: (1) detailed feedback of baseline data and discussion (utilizing audit and feedback), (2) why systematic reviews, analgesic league tables and choice of drugs to develop an analgesic algorithm (see Figure 1), (3) principles of evidence based health care (EBHC), including critical appraisal and (4) facilitation and change workshop. The findings revealed no significant differences in pain level or drug use between the intervention and control wards. However, the control wards also changed during the control period. Possible explanations for this are discussed. When looking at changes compared with baseline, both intervention and control wards increased their use of algorithm drugs and reduced use of non-algorithm drugs during the study. No effects were found on pain in the intervention wards. Pain ratings at rest since surgery, on movement since surgery and worst pain on movement were significantly reduced compared with baseline in the control wards. Although there are many pressures to utilize a randomized-controlled trial study design in the culture of evidence-based health care, there will be times, especially when implementing complex changes in practice that other types of design should be considered.


Reproduction results and offspring performance after non-surgical embryo transfer in pigs.
Increased interest in transfer of valuable genetic material around the world with minimal health risks has stimulated the development of non-surgical embryo transfer (nsET) technologies in pigs. Experimental evidence shows that nsET without sedation of the recipients is now feasible. The goal of this study, therefore, was to evaluate a method of nsET under commercial conditions. The experiment included 135 donor gilts and 45 multiparous recipient sows. Ovulation was induced in both donors and recipients, and nsET was performed using the Swinlet catheter. Donor gilts averaged 16.5 (7-45) corpora lutea, but this depended on age of the donor (P < 0.05). An average of 10.1 transferable blastocysts was recovered per donor, and the recovery rate was 84%. For 44 nsET, 14 recipients (31%) came into estrous before Day 23 after ovulation, 7 recipients (16%) came into estrous between Days 23 and 30, 3 recipients (6.8%) came into estrous between Days 39 and 48, 2 recipients (4.5%) had a late abortion. Finally, 18 of 44 recipients (41%) resulted in successful births, with an average liter size of 7.2 +/- 2.8. Birth weight of nsET piglets were 0.2 kg more than control piglets, but depended on litter size ((P < 0.05). The sex-ratio was not different from 50%. No anatomical abnormalities were observed in the offspring of nsET. Of the recipients that did not become pregnant from nsET, 91% became pregnant after insemination in the next estrous. Gilts born from nsET gave on average 12.4 +/- 3.0 total born piglets in their first pregnancy. In conclusion, the nsET procedure used in this study can be applied in practice without the need for special facilities, such as surgical and anesthesia equipment.


Venous sinus stenting for idiopathic intracranial hypertension is not associated with cortical venous occlusion.
The effect of dural venous sinus stenting has been investigated for the treatment of idiopathic intracranial hypertension (IIH) but the effect of stenting on the long-term patency of the cortical draining veins, especially the vein of Labbé (VOL), remains unknown. We reviewed our database of 38 patients with IIH with 41 stented dural venous sinuses between October 2006 and December 2014. Demographic, clinical, and radiological data were reviewed. Follow-up catheter angiographic data were included when available. Stent placement spanned the ostium of the VOL in 35 patients (92.1%), with no immediate effect on the drainage of the VOL. Follow-up angiography (mean 35.1 months, range 1.7-80.7 months) was available in 24 patients, 21 of whom had stents spanning the VOL ostium. The VOL remained patent without occlusion or drainage alteration in all 21 patients. There were no immediate or long-term intracranial complications. Dural venous sinus stenting for patients with IIH does not affect the immediate or long-term patency of the VOL and is not associated with intracranial complications.


Increased respiratory neural drive and work of breathing in exercise-induced laryngeal obstruction.
Exercise-induced laryngeal obstruction (EILO), a phenomenon in which the larynx closes inappropriately during physical activity, is a prevalent cause of exertional dyspnea in young individuals. The physiological ventilatory impact of EILO and its relationship to dyspnea are poorly understood. The objective of this study was to evaluate exercise-related changes in laryngeal aperture on ventilation, pulmonary mechanics, and respiratory neural drive. We prospectively evaluated 12 subjects (6 with EILO and 6 healthy age- and gender-matched controls). Subjects underwent baseline spirometry and a symptom-limited incremental exercise test with simultaneous and synchronized recording of endoscopic video and gastric, esophageal, and transdiaphragmatic pressures, diaphragm electromyography, and respiratory airflow. The EILO and control groups had similar peak work rates and minute ventilation (V̇e) (work rate: 227 ± 35 vs. 237 ± 35 W; V̇e: 103 ± 20 vs. 98 ± 23 l/min; P > 0.05). At submaximal work rates (140-240 W), subjects with EILO demonstrated increased work of breathing ( P < 0.05) and respiratory neural drive ( P < 0.05), developing in close temporal association with onset of endoscopic evidence of laryngeal closure ( P < 0.05). Unexpectedly, a ventilatory increase ( P < 0.05), driven by augmented tidal volume ( P < 0.05), was seen in subjects with EILO before the onset of laryngeal closure; there were however no differences in dyspnea intensity between groups. Using simultaneous measurements of respiratory mechanics and diaphragm electromyography with endoscopic video, we demonstrate, for the first time, increased work of breathing and respiratory neural drive in association with the development of EILO. Future detailed investigations are now needed to understand the role of upper airway closure in causing exertional dyspnea and exercise limitation. NEW & NOTEWORTHY Exercise-induced laryngeal obstruction is a prevalent cause of exertional dyspnea in young individuals; yet, how laryngeal closure affects breathing is unknown. In this study we synchronized endoscopic video with respiratory physiological measurements, thus providing the first detailed commensurate assessment of respiratory mechanics and neural drive in relation to laryngeal closure. Laryngeal closure was associated with increased work of breathing and respiratory neural drive preceded by an augmented tidal volume and a rise in minute ventilation.


The relationship between caregiver's strain and social support among mothers with intellectually disabled children.
To explore caregiver's strain, the relationship between social support and caregiver's strain and the predictors of caregiver's strain among mothers with school-aged intellectually disabled children in Taiwan. Strain is a common condition among mothers who take care of intellectually disabled children; this correspondingly reduces their ability to care for children, thereby affecting the functioning of the entire family. Yet, there have been very few studies on caregivers of intellectually disabled children of school age. Cross-section correlational design. Data collection consisted of face-to-face interviews combined with a structured questionnaire. Instruments employed were the Caregiver Strain Index, Social Support Scale and three open-ended questions. In total, 127 mothers completed the questionnaire. Results showed that mothers with intellectually disabled children had a rather high level of strain and received inadequate social support. Social support and strain had a significant and negative correlation. Stepwise regression analysis revealed that mothers' health status, social support and amount of time spent as a caregiver, as well as the intellectually disabled children's dependent degree of daily living activity, were major predictors of caregiver's strain, which accounted for 38.4% of the total variance. The results provide a guide for healthcare professionals in designing effective interventions and preventive care to reduce the level of strain in mothers with intellectually disabled children. This, in turn, could improve the quality of life of the mother and her family. In Taiwan, care of intellectually disabled children is primarily provided by family members. Therefore, we should emphasise family-centred care to enable healthcare professionals to become more effective as case managers in local clinics, schools and communities.


Economic Evaluation of Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer in the United States.
Recently, the DESTINY-Breast04 trial revealed that significant benefits in both overall survival (OS) and progression-free survival (PFS) in patients with HER2-low advanced or metastatic breast cancer treated with trastuzumab deruxtecan (T-DXd) compared with chemotherapy. The current study assessed the cost-effectiveness of T-DXd from the perspective of the United States payer. We developed a partitioned survival model to project the disease course of breast cancer. The OS and PFS data were derived from the DESTINY-Breast04 trial. We extrapolate the survival data beyond the follow-up time to assess the long-term survival prognosis. Direct medical costs and utility data were collected. The incremental cost-utility ratio (ICUR) was the primary outcome that evaluated the cost-effectiveness of a therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty of outputs. In the base-case, the ICUR of T-DXd versus chemotherapy is $346,571.8/QALY and $337,789.4/QALY for all patients group and hormone-receptor-positive (HR+) subgroup, respectively. One-way sensitivity analyses revealed that the hazard ratio of OS, the unit cost of T-DXd, and body weight had a relatively large impact on the base-case result. Probabilistic sensitivity analyses showed that the likelihood that T-DXd was cost-effective is 14.5% and 12.6% for all patients group and HR+ subgroup, respectively. The cost-effectiveness analysis suggested that, at current price, trastuzumab deruxtecan is unlikely to be a preferred option for patients with HER2-low breast cancer at a threshold of $150,000/QALY from a US payer perspective.


Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients.
To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin. We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m(2) by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m(2) in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m(2) followed immediately by docetaxel 70 mg/m(2) in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography. No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1. 7-fold and 1.9-fold higher (P <.05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 +/- 150 ng/mL*h) was significantly higher (P <.01) than the corresponding values after epirubicin administered either as a single agent (692 +/- 46 ng/mL*h) or in combination with docetaxel (848 +/- 237 ng/mL*h). There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.


["Anti-stigma campaign from below" at schools--experience of the initiative "Irre menschlich Hamburg e.V."].
In the process of stigmatisation psychiatry is not neutral but it is up-to-date as well as historically involved. That is why it is responsible to influence not only the social perception of psychiatry but also the public picture of mentally disturbed people in a positive way. Doing so it is dependent on the help of psychosis-experienced persons and relatives. Only working together a plausible enlightenment, that points beyond the status quo, can be achieved. Anti-stigma work must critically reflect the interactions in psychiatry itself. After an analysis of the different concepts of stigmatisation and anti-stigma work there follows the evaluation of an information campaign at schools in Hamburg, which emerged from the Hamburg psychosis seminar. The personal meeting of students and psychosis experienced persons is of immediate importance. In addition to that media about the subject "being different, madness, mental disturbation" are being placed at the teachers disposal according to their wishes. In the meantime experience is there of more then 50 teaching units in primary advanced and secondary education as well as of a special open day attended by over 500 students. The response of students and teachers is definitely positive. For the psychosis experienced persons involved there is a special benefit in the sense of empowerment. The more health politically based motives of the anti-stigma work have meanwhile been completed by educational justifications. This way of open meeting is also being discussed as a completion to the symptom based early diagnosis.


Examining the effect of patient-centred care on outcomes.
Within patient-centered care (PCC), the individual is viewed as an active member of the healthcare team. While there has been recent interest in conducting systematic reviews to examine the effectiveness of PCC interventions, various studies fall short in explaining the type of intervention most effective in producing significant changes to desired outcomes. The purpose of this systematic review was to determine the characteristics of PCC interventions that have demonstrated effectiveness in enhancing the quality of care and performance of self-care behaviours. A systematic review of 40 studies that addressed PCC interventions, included samples over the age of 18 years, and were published between 1995 and 2014 was performed. Descriptive statistics were used to delineate study, participant, and intervention characteristics. Results suggest PCC-based interventions are not effective when delivered to individuals living with chronic illnesses.


Measuring whole body inert gas wash-out.
Quantifying inert gas wash-out is crucial to understanding the pathophysiology of decompression sickness. In this study, we developed a portable closed-circuit device for measuring inert gas wash-out and validated its precision and accuracy both with and without human subjects. We developed an exhalate monitor with sensors for volume, temperature, water vapor and oxygen. Inert gas volume was extrapolated from these inputs using the ideal gas law. The device's ability to detect volume differences while connected to a breathing machine was analysed by injecting a given gas volume eight times. One hundred and seventy-two coupled before-and-after measurements were then compared with a paired t-test. Drift in measured inert gas volume during unlabored breathing was evaluated in three subjects at rest using multilevel linear regression. A quasi-experimental cross-over study with the same subjects was conducted to evaluate the device's ability to detect inert gas changes in relation to diving interventions and simulate power. The difference between the injected volume (1,996 ml) and the device's measured volume (1,986 ml) was -10 ml. The 95% confidence interval (CI) for the measured volume was 1,969 to 2,003 ml. Mean drift during a 43 min period of unlaboured breathing was -19 ml, (95% CI, -37 to -1). Our power simulation, based on a cross-over study design, determined a sample size of two subjects to detect a true mean difference of total inert gas wash-out volume of 100 ml. We present a portable device with acceptable precision and accuracy to measure inert gas wash-out differences that may be physiologically relevant in the pathophysiology of decompression sickness.


Transition from APAP to CPAP may be a cost-effective health intervention in OSA patients.
Obstructive sleep apnea (OSA) is a common disorder associated with a significant economic burden. Continuous positive airway pressure (CPAP) and auto-titrating positive airway pressure (APAP) are recognized therapeutic options in patients with OSA, although treatment costs are higher with APAP. We conducted a study aimed at evaluating the effectiveness and potential cost savings resulting from the implementation of a protocol guiding the transition to CPAP in OSA patients previously treated with APAP. This prospective study included patients with OSA under APAP who were followed up at the Sleep Medicine outpatient clinic of a tertiary referral hospital between January 2019 and January 2021. Treatment was switched to CPAP in patients who met the following criteria: satisfactory adaptation and adherence to APAP, residual apnea-hypopnea index (AHI) of < 5/hour, and no relevant air leaks. APAP and CPAP outcomes were compared and an estimate of the savings obtained by the transition from APAP to CPAP was calculated. Ninety-three patients were included in the study. APAP and CPAP were both effective in correcting obstructive events and improving daytime sleepiness. No significant differences were found regarding treatment adherence and tolerance between both PAP modalities. The selection of fixed-pressure CPAP through 90th or 95th percentile APAP pressure proved to be effective and an alternative strategy to titration polysomnography. At the end of this two-year study, the transition from APAP to CPAP enabled savings of at least 10,353€. The transition from APAP to CPAP may be an effective, well-tolerated, safe, and cost-saving strategy in patients with OSA.


Novel serum biomarkers for detection of excessive alcohol use.
Construct interview that correctly identifies those with alcohol use disorder have limitation, especially when the subjects are motivated to minimize the magnitude of drinking behavior. Current laboratory tests to detect excessive alcohol consumption are limited by marginal sensitivity/specificity. Excessive drinking has been shown to affect several organ systems, which may be reflected in changes in quantity of plasma proteins. Our aim was to employ novel proteomic analyses to identify potential markers for excessive alcohol use. A prospective case-control study included 49 controls and 54 excessive drinkers (discovery cohort). The serum proteomic analyses in these subjects were performed, and the results were tested in the verification cohort (40 controls and 40 excessive drinkers). Using the appropriate cutoff and confirmation with ELISA, we identified 4 proteins which were significantly elevated in the serum of excessive drinkers: AT-rich interactive domain-containing protein 4B (ARID4B), phosphatidylcholine-sterol acyltransferase (LCAT), hepatocyte growth factor-like protein (MST1), and ADP-ribosylation factor 6 (ARL6). The performance of the conventional markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], percentage of carbohydrate-deficient transferrin [%CDT], and mean corpuscular volume [MCV]) discriminating between excessive alcohol use and controls had an area under the curve (AUC) ranging from 0.21 (ALT) to 0.67 (MCV). The AUC of these novel proteins showed the improvement in the detection of excessive drinkers compared to conventional laboratory tests, ranging from 0.73 (for ARID4B) to 0.86 (for ARL6). We have identified 4 novel proteins that can discern subjects with excessive alcohol use. Further studies are needed to determine the clinical implications of these markers to detect excessive alcohol use and confirm abstinence.


Physical and sexual violence and health care utilization in HIV-infected persons with alcohol problems.
We examined interpersonal violence and its association with health care utilization and substance use severity among a cohort of 349 HIV-infected men and women with histories of alcohol problems assessed biannually up to 36 months. Data included demographics, lifetime interpersonal violence histories, age at first violence exposure, recent violence (prior six months), substance use severity and health care utilization (ambulatory visits, Emergency Department (ED) visits, hospitalizations) and adherence to HIV medication. Kaplan-Meier survival curves estimated the proportion of subjects experiencing recent violence. Generalized estimating equation regression models evaluated the relationship between recent violence, utilization and substance use severity over time, controlling for demographics, CD4 counts and depressive symptoms. Subject characteristics included: 79% male; mean age 41 years; 44% black, 33% white and 23% other. Eighty percent of subjects reported lifetime interpersonal violence: 40% physical violence alone, and 40% sexual violence with or without physical violence. First violence occurred prior to age 13 in 46%. Twenty-four (41%) of subjects reported recent violence by 24 and 36 months, respectively. In multivariate analyses, recent violence was associated with more ambulatory visits, ED visits and hospitalizations and worse substance use severity, but not medication adherence. Due to the high incidence and associated increased health care services utilization, violence prevention interventions should be considered for HIV-infected patients with a history of alcohol problems.


Antibody suspension bead arrays.
Alongside the increasing availability of affinity reagents, antibody microarrays have been developed to become a powerful tool to screen for target proteins in complex samples. Besides multiplexed sandwich immunoassays, the application of directly applying labeled sample onto arrays with immobilized capture reagents offers an approach to facilitate a systematic, high-throughput analysis of body fluids such as serum or plasma. An alternative to commonly used planar arrays has become available in form of a system based on color-coded beads for the creation of antibody arrays in suspension. The assay procedure offers an uncomplicated option to screen larger numbers of serum or plasma samples with variable sets of capture reagents. In addition, the established procedure of whole sample biotinylation circumvents the purification steps, which are generally required to remove excess labeling substance. We have shown that this assay system allows detecting proteins down into lower pico-molar and higher picogram per milliliter levels with dynamic ranges over three orders of magnitude. Presently, this workflow enables the profiling of 384 clinical samples for up to 100 proteins per assay.


Kaempferol attenuates the glutamate-induced oxidative stress in mouse-derived hippocampal neuronal HT22 cells.
It is thought that the neuronal cell loss caused by oxidative stress is the primary mechanism underlying the pathogenesis of several neurodegenerative disorders. Glutamate is an endogenous neurotransmitter, but at high concentrations it can act as a neurotoxicant by increasing the intracellular levels of reactive oxygen species (ROS). Therefore, the development of factors that can attenuate glutamate-induced oxidative stress in neuronal cells is a good strategy by which new drugs could be discovered that may treat or prevent neurodegenerative diseases. Here, the neuroprotective effects of kaempferol (KF) isolated from the stems of butterbur (Petasites japonicus) were examined in glutamate-treated hippocampal neuronal cells (HT22). The administration of KF (25 μM) resulted in a significant increase in cell viability (105.18 ± 7.48%) compared with the control (100.00 ± 3.05%), while glutamate (5 mM) reduced cell viability by 39.94 ± 1.61%. The glutamate-induced calcium (Ca(2+)) influx (1.93 ± 0.08-fold) was significantly reduced by 0.89 ± 0.02-fold following the administration of 25 μM KF. Additionally, when HT22 cells were stressed with excessive glutamate, there was a 3.70 ± 0.01-fold increase in intracellular ROS generation, even though this was effectively attenuated by KF (25 μM, 0.72 ± 0.01-fold). The protective effects of KF in HT22 cells were later confirmed using a lactate dehydrogenase (LDH) assay and a FITC-annexin V/propidium iodide double staining procedure. These findings also revealed that the neuroprotective effects of KF are a result of the regulation of the expression levels of proteins, such as Bcl-2, Bid, apoptosis-inducing factor (AIF), and mitogen-activated protein kinase (MAPK). This is the first report to investigate the neuroprotective influence of KF in glutamate-treated HT22 cells. These data demonstrate that KF may be a useful candidate for pharmacological therapies that can prevent and treat neurodegenerative diseases such as Alzheimer's disease (AD).


Quantitative analysis of the 3D cell shape changes driving soybean germination.
Seed germination is central to plant establishment and is the starting point for the majority of world agriculture. This transition from seed to seedling has been extensively studied at an organ level, while few studies have examined the cellular events which underlie it. Reports in the model species Arabidopsis have identified a radicle-derived wave of cell expansion underlying the germination process. Whether this spatiotemporal pattern of cell expansion is specific to this model plant or conserved in other species remains unknown. Here we examined the 3D cell anisotropy driving germination in soybean. By examining changes in cell shape at two positions along the length of the axis over time, preferential growth was observed in the portion of the axis closest to the radicle. A gradient of cell size was observed across the cortical cell layers of the soybean axis, and differences in starting cell size translated into differential relative growth rates across cell layers where larger cells showed greater relative growth rates than smaller cells. Differences in cell position-specific cell anisotropy were also observed. These data demonstrate that a radicle-derived growth pattern is present in the crop species soybean, and reveal the presence of a complex cellular organization in this hypocotyl which show cell type-specific anisotropy diving germination.


Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability.
The incidences of microsatellite instability (MSI) and underlying DNA mismatch repair (MMR) defects in pancreatic carcinogenesis have not been well established. We analyzed 100 sporadic and 3 hereditary pancreatic ductal adenocarcinomas for MSI, and high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L) tumors were further analyzed for frameshift mutations of possible target genes and for promoter methylation and mutation of DNA MMR genes, including hMLH1, hMSH2, hMSH3, and hMSH6 genes. Among the 100 sporadic tumors, 13 (13%) were MSI-H, 13 (13%) were MSI-L, and 74 (74%) were microsatellite stable (MSS) tumors. All of the three hereditary tumors from hereditary nonpolyposis colorectal cancer (HNPCC) patients were MSI-H. MSI-H tumors were significantly associated with poor differentiation and the presence of wild-type K-RAS and p53 genes. Patients with MSI-H tumors had a significantly longer overall survival time than did those with MSI-L or MSS tumors (P = 0.0057). Frameshift mutations of hMSH3, hMLH3, BRCA-2, TGF-beta type II receptor, and BAX genes were detected in MSI-H tumors. Hypermethylation of the hMLH1 promoter was observed in 6 (46%) of the 13 sporadic MSI-H tumors but not in any of the 3 hereditary MSI-H tumors or 13 MSI-L tumors. All of the 3 HNPCC cases had germ-line hMLH1 mutation accompanied by loss of heterogeneity or other mutation in the tumor. Our results suggest that pancreatic carcinomas with MSI-H represent a distinctive oncogenic pathway because they exhibit peculiar clinical, pathological, and molecular characteristics. Our results also suggest the principal involvement of epigenetic or genetic inactivation of the hMLH1 gene in the pathogenesis of pancreatic carcinoma with MSI-H.


Sustainable metropolitan areas perspectives through assessment of the existing waste management strategies.
Human activities are considered among the main producers of any kind of pollution. This paper, through a Driver-Pressure-State-Impact-Response (DPSIR) model analyses, focuses on the evaluation and assessment of the existing practices, procedures, and results obtained in order to determine whether the municipal solid waste (MSW) management implemented in three major Greek municipalities in the greater urban area of Attica, namely the municipalities of Nea Smirni, Vyronas, and Piraeus, could be considered viable and sustainable. The evaluation indicated that MSW in Greek cities have reduced over the last years, also suggesting a steady downward trend, which could be considered consistent with that of the per capita incomes in Greece due to the extended economic austerity, while at the same time the recycling indicator seems to optimize. The results are very useful for policymakers and local authorities towards taking actions related to the targets set from the circular economy strategies as well as the targets set from United Nation Development Program and the European Green Deal Strategy.


The clinical application of the biopsychosocial model in mental health: a research critique.
Engel applied the term biopsychosocial to medicine to emphasize the need to take into account the psychologic and social aspects of medical practice. After an overview of the history of the biopsychosocial (BPS) model, we review criticisms of the model to reformulate its deficiencies and then analyze its application in mental health care. The objectives of this paper are 4-fold: (1) to examine the use of the BPS model since Engel's 1977 article to the present; (2) to examine the reasons for the popularity of the BPS model as well as the problems it faces when applied to mental health care; (3) to introduce two instruments, the International Classification of Functioning, Disability, and Health and the INTERMED, which implement the BPS model; and (4) to show why the BPS model is not yet a model of mental health practice. A total of 62 publications were retrieved and reviewed in the ScienceDirect, PubMed, and Scopus databases, and 32 of them were eventually included in this review. This is the first review of the studies published that applied the BPS model in mental health in the last 33 yrs. These criticisms are used to construct a more workable vision of the BPS model of clinical practice.


Indomethacin induces increase in gastric epithelial tight junction permeability via redistribution of occludin and activation of p38 MAPK in MKN-28 Cells.
Tight Junctions (TJ) create a paracellular barrier that is compromised when nonsteriodal anti-inflammatory drugs (NSAIDs) injure the gastric epithelium, leading to increased permeability. However, the mechanism of NSAID-induced gastric injury is unclear. Here, we examined the effect of indomethacin on barrier function and TJ in gastric MKN-28 cells. In concentration response studies, 500 µm indomethacin induced a significant decrease in transepithelial resistance (TER; 380 vs. 220 Ω·cm(2) for control and indomethacin-treated cells respectively, p < 0.05), and increased dextran permeability by 0.2 vs 1.2 g/l (p < 0.05). These changes in barrier function were completely ameliorated by the p38 MAPK inhibitor (SB-203580) but not by JNK inhibitor (SP-600125) or MEK/ERK inhibitor (PD-98059). SiRNA knock down of p38 MAPK prevented the loss of barrier function caused by indomethacin in MKN-28 cells. Western analyses of TJ proteins revealed that expression of occludin was reduced by indomethacin, whereas there was no change in other TJ proteins. The loss of occludin expression induced by indomethacin was prevented by inhibition of p38 MAPK but not JNK or ERK and also by siRNA of p38 MAPK. Immunofluorescence revealed disruption of occludin localization at the site of the tight junction in indomethacin-treated cells, and this was attenuated by inhibition of p38 MAPK. NSAID injury to murine gastric mucosa on Ussing chambers revealed that indomethacin caused a significant drop in TER and increased paracellular permeability. Pretreatment with the p38 MAPK inhibitor significantly attenuated the disruption of barrier function, but JNK and MEK/ERK inhibition had no effect. Western blot analysis on gastric mucosa reveled loss of TJ protein occludin by indomethacin, which was prevented by inhibition of p38 MAPK. This data suggests that indomethacin compromises the gastric epithelial barrier via p38 MAPK inducing occludin alterations in the TJs.


Using a Consensus-Driven Approach to Incorporate Holistic Review Into an Internal Medicine Residency Program.
Despite growing interest in incorporating holistic review within residency admissions, implementation by residency programs remains challenging. To incorporate holistic review into the internal medicine residency program at the University of Wisconsin and to report initial feasibility and acceptability data. During the 2020-2021 application cycle, residency stakeholders performed a consensus-driven process to identify highly valued applicant attributes. We used a holistic review process to identify the presence of these attributes among applicants and updated our rank list algorithm to incorporate these attributes. We modified our interview screening criteria and rank list algorithm to de-emphasize other metrics. We surveyed stakeholders to assess time required for this process and compared our final rank list to what it would have been using our prior system. The final list of 10 prioritized applicant attributes included extraordinary leadership, community service, and grit, among others. Among 25 matched residents, 8 (32%) were recognized to have exceptional achievement within one of these 10 attributes. Four members of the incoming intern class (16%) would have been in a rank position lower than our historical matched resident cutoff had they not received additional points for these attributes. Faculty reported that holistic review of applications took an additional 3.8 minutes on average. It was felt that current application materials limit the ability to implement a fully holistic review. The addition of holistic review to our residency admissions process was achieved using a consensus-driven approach and showed favorable feasibility and acceptability data.


A cluster randomised trial testing an intervention to improve parents' recognition of their child's weight status: study protocol.
Parents typically do not recognise their child's weight status accurately according to clinical criteria, and thus may not take appropriate action if their child is overweight. We developed a novel visual intervention designed to improve parental perceptions of child weight status according to clinical criteria for children aged 4-5 and 10-11 years. The Map Me intervention comprises age- and sex-specific body image scales of known body mass index and supporting information about the health risks of childhood overweight. This cluster randomised trial will test the effectiveness of the Map Me intervention. Primary schools will be randomised to: paper-based Map Me; web-based Map Me; no information (control). Parents of reception (4-5 years) and year 6 (10-11 years) children attending the schools will be recruited. The study will work with the National Child Measurement Programme which measures the height and weight of these year groups and provides feedback to parents about their child's weight status. Before receiving the feedback, parents will complete a questionnaire which includes assessment of their perception of their child's weight status and knowledge of the health consequences of childhood overweight. The control group will provide pre-intervention data with assessment soon after recruitment; the intervention groups will provide post-intervention data after access to Map Me for one month. The study will subsequently obtain the child height and weight measurements from the National Child Measurement Programme. Families will be followed-up by the study team at 12 months. The primary outcome is any difference in accuracy in parental perception of child weight status between pre-intervention and post-intervention at one month. The secondary outcomes include differences in parent knowledge, intention to change lifestyle behaviours and/or seek advice or support, perceived control, action planning, coping planning, and child weight status at 12 month follow-up. The Map Me tool has potential to make a positive impact on children's health at a population level by introducing it into current intervention programmes to improve accuracy of parental perception of child's weight status. This trial will inform the action of researchers, educators, health professionals and policy makers. Current Controlled Trials ISRCTN91136472. Registered 3 May 2013.


Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis.
Macrophages play essential roles in immunity and homeostasis. As professional scavengers, macrophages phagocytose microbes and apoptotic and necrotic cells and take up modified lipoprotein particles. These functions require tightly regulated mechanisms for the processing and disposal of cellular lipids. Under pathological conditions, arterial wall macrophages become foam cells by accumulating large amounts of cholesterol, contributing to the development of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily of transcription factors that have emerged as key regulators of macrophage homeostasis. PPARs and LXRs control transcriptional programs involved in processes of lipid uptake and efflux, lipogenesis, and lipoprotein metabolism. In addition, PPARs and LXRs negatively regulate transcriptional programs involved in the development of inflammatory responses. This review summarizes recent efforts to decode the differential and overlapping roles of PPARs and LXRs in the context of macrophage lipid homeostasis and the control of inflammation.


Diet and breast cancer: can dietary factors influence survival?
Breast cancer accounts for over one third of invasive cancers in women. Earlier detection and improved initial treatments have resulted in an increasing number of women who have completed standard treatments but who remain at risk for breast cancer recurrence or early death. Epidemiological studies have linked diet composition with prognosis, and many women attempt to modify their diets and improve nutritional status following diagnosis The hypothesis that dietary factors may reduce risk for secondary cancer events and increase survival in this population is currently under study in two large randomized clinical trials: the Women's Intervention Nutrition Study (WINS) and the Women's Healthy Eating and Living (WHEL) Study. The WHEL Study is testing the effect of a diet high in vegetables, fruit, and fiber, and low in fat, on disease-free survival in women with early stage breast cancer. Hypothesized mechanisms include effects of diet modification on gonadal hormones, retinoid-like activities of carotenoids, and other protective effects of biologically active dietary constituents.


Successful imiquimod treatment of multiple basal cell carcinomas after radiation therapy for Hodgkin's disease.
We present a case of a 55-year-old male patient who developed five basal cell carcinomas 23 years after radiation therapy of Hodgkin's disease. In 1980 he received radiation therapy twice. Due to relapses, he was treated with aggressive polychemotherapy and underwent autologous stem cell transplantation, which then led to complete remission. Until now he is in complete remission. However, multiple superficial basal cell carcinomas have developed on irradiation fields that have been successfully treated by imiquimod.


A DFT study of the structures, stabilities and redox behaviour of the major surfaces of magnetite Fe₃O₄.
The renewed interest in magnetite (Fe3O4) as a major phase in different types of catalysts has led us to study the oxidation-reduction behaviour of its most prominent surfaces. We have employed computer modelling techniques based on the density functional theory to calculate the geometries and surface free energies of a number of surfaces at different compositions, including the stoichiometric plane, and those with a deficiency or excess of oxygen atoms. The most stable surfaces are the (001) and (111), leading to a cubic Fe3O4 crystal morphology with truncated corners under equilibrium conditions. The scanning tunnelling microscopy images of the different terminations of the (001) and (111) stoichiometric surfaces were calculated and compared with previous reports. Under reducing conditions, the creation of oxygen vacancies in the surface leads to the formation of reduced Fe species in the surface in the vicinity of the vacant oxygen. The (001) surface is slightly more prone to reduction than the (111), due to the higher stabilisation upon relaxation of the atoms around the oxygen vacancy, but molecular oxygen adsorbs preferentially at the (111) surface. In both oxidized surfaces, the oxygen atoms are located on bridge positions between two surface iron atoms, from which they attract electron density. The oxidised state is thermodynamically favourable with respect to the stoichiometric surfaces under ambient conditions, although not under the conditions when bulk Fe3O4 is thermodynamically stable with respect to Fe2O3. This finding is important in the interpretation of the catalytic properties of Fe3O4 due to the presence of oxidised species under experimental conditions.


Monkeypox: what do dental professionals need to know?
Infection control is critical for the safe delivery of dental care. Infection control practices must be responsive to emerging and re-emerging infectious diseases and outbreaks, as was clearly seen during the peak of the COVID-19 pandemic. An emerging global outbreak of the monkeypox virus has again raised potential challenges for infection control in dentistry. Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. Previously, cases were mostly seen following contact with infected animals in Central and West Africa, with limited human-to-human transmission within and outside of these areas. However, since May 2022, sustained human-to-human transmission has occurred globally. Monkeypox can be transmitted via close contact with an infected person, contaminated objects and surfaces, or by droplets and possibly aerosols, which is therefore of potential importance to dental settings. This article discusses the relevance of monkeypox to dental professionals, the typical presentation of the disease, its potential impact on infection prevention and control practices and the delivery of dental services. The current monkeypox outbreak highlights the need for a more sustained programme of research into dental infection control that can provide a solid evidence base to underpin preparedness planning for future outbreaks and pandemics.


Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.


EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas.
Mutations at codon 641 of EZH2 are recurrent in germinal center B cell lymphomas, and the most common variants lead to altered EZH2 enzymatic activity and enhanced tri-methylation of histone H3 at lysine 27, a repressive chromatin modification. As an initial step toward screening patients for cancer genotype-directed therapy, we developed a screening assay for EZH2 codon 641 mutations amenable for testing formalin-fixed clinical specimens, based on the sensitive SNaPshot single nucleotide extension technology. We detected EZH2 mutations in 12/55 (22%) follicular lymphomas (FL), 5/35 (14%) diffuse large B cell lymphomas with a germinal center immunophenotype (GCB-DLBCL), and 2/11 (18%) high grade B cell lymphomas with concurrent rearrangements of BCL2 and MYC. No EZH2 mutations were detected in cases of Burkitt lymphoma (0/23). EZH2 mutations were frequently associated with the presence of BCL2 rearrangement (BCL2-R) in both the FL (28% of BCL-R cases versus 0% of BCL2-WT cases, p<0.05) and GCB-DLBCL groups (33% of BCL2-R cases versus 4% of BCL2-WT cases, p<0.04), and across all lymphoma types excluding BL (27% of BCL2-R cases versus 3% of BCL2-WT cases, p<0.003). We confirmed gain-of-function activity for all previously reported EZH2 codon 641 mutation variants. Our findings suggest that EZH2 mutations constitute an additional genetic "hit" in many BCL2-rearranged germinal center B cell lymphomas. Our work may be helpful in the selection of lymphoma patients for future trials of pharmacologic agents targeting EZH2 and EZH2-regulated pathways.


The marine fishes of St Eustatius Island, northeastern Caribbean: an annotated, photographic catalog.
Sint Eustatius (Statia) is a 21 km2 island situated in the northeastern Caribbean Sea. The most recent published sources of information on that island's marine fish fauna is in two non-governmental organization reports from 2015-17 related to the formation of a marine reserve. The species-list in the 2017 report was based on field research in 2013-15 using SCUBA diving surveys, shallow "baited underwater video surveys" (BRUVs), and data from fishery surveys and scientific collections over the preceding century. That checklist comprised 304 species of shallow (mostly) and deep-water fishes. In 2017 the Smithsonian Deep Reef Observation Project surveyed deep-reef fishes at Statia using the crewed submersible Curasub. That effort recorded 120 species, including 59 new occurrences records. In March-May 2020, two experienced citizen scientists completed 62 SCUBA dives there and recorded 244 shallow species, 40 of them new records for Statia. The 2017-2020 research effort increased the number of species known from the island by 33.6% to 406. Here we present an updated catalog of that marine fish fauna, including voucher photographs of 280 species recorded there in 2017 and 2020. The Statia reef-fish fauna likely is incompletely documented as it has few small, shallow, cryptobenthic species, which are a major component of the regional fauna. A lack of targeted sampling is probably the major factor explaining that deficit, although a limited range of benthic marine habitats may also be contributing.


Glycemic, insulinemic, and appetite responses of patients with type 2 diabetes to commonly consumed breads.
The purpose of this study was to identify the breads most commonly consumed by adults with type 2 diabetes (T2DM) and then examine the postprandial glycemic, insulinemic, and appetite responses that these breads elicit. One hundred people with T2DM were surveyed to identify the varieties of bread they most frequently consumed. According to a randomized crossover design, 11 fasting participants with T2DM consumed 50 g of available carbohydrate from 4 breads. Glucose and insulin concentrations and appetite ratings were determined over 270 minutes. Three commonly consumed varieties (white, whole wheat buttermilk, whole grain) identified in the survey-plus a lower-glycemic-index "control" bread (pumpernickel rye)-were tested in the second phase. Despite perceived differences between "brown" and "white" breads, the white, whole wheat buttermilk, and wholegrain breads promoted similar glycemic and insulinemic responses. Pumpernickel bread resulted in a significantly lower peak glucose (P < .01) than all other breads and a lower peak insulin (P < .001) than white or wholegrain bread. Similar appetite responses were found with all 4 breads. Adults with T2DM are choosing a variety of breads with perceived differential effects on glycemic, insulinemic, and appetite responses. Appreciable benefits, however, are not conferred by the commonly consumed breads. If breads known to promote favorable metabolic responses are unavailable, the primary emphasis in education should be placed on portion control. Conveying this information to patients is crucial if nutrition education is to achieve its aim of empowering individuals to manage their diabetes through their food choices.


Growing older with cerebral palsy: insiders' perspectives.
Research has shown that adults with cerebral palsy (CP) lose functional abilities earlier than persons who are able-bodied. Because CP is a lifespan disability, developmental therapists should be aware of these changes. We used descriptive phenomenology to understand the unique, lived experiences of adults growing older with CP. Data were gathered through in-depth, semistructured interviews. Open-ended questions asked what it was like to age with CP, how these experiences were understood, how strategies were used to cope with changes, and what are the meanings of these experiences. A theme, Awareness, Acceptance, and Action, emerged from the data analysis. Participants were aware that their bodies were deteriorating quicker than those of peers who are able-bodied. They developed acceptance that hastened actions toward improving their quality of life. These findings provide insights for pediatric therapists who work with children with CP about what may be important to their clients as they grow older.


Urinary leukotriene E4 excretion: a biomarker of inflammatory bowel disease activity.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders collectively referred to as inflammatory bowel diseases (IBD). Cysteinyl leukotrienes are proinflammatory 5-lipoxygenase-derived products that play a major role in the immune and inflammatory response. Consequently, they may be involved in the pathogenesis of IBD. The aim of this study was therefore to evaluate 1) the urinary excretion of leukotriene E(4) (LTE(4)) in IBD patients and healthy volunteers, and 2) the association between LTE(4) production and the activity (relapse/remission) of the disease. IBD patients and healthy volunteers were prospectively recruited. CD and UC activity was determined on inclusion with the Crohn's Disease Activity Index and Clinical Activity Index, respectively. Urine was collected and the urinary excretion of LTE(4) was measured by liquid chromatography tandem mass spectrometry. 32 CD patients, 28 UC patients, and 30 controls were enrolled in the study. LTE(4) urinary excretion was significantly increased (P < 0.01) in CD [52.0 pg/mg creatinine (10th-90th percentiles: 26.2-148.0)] and UC [64.1 pg/mg creatinine (10th-90th percentiles: 26.7-178.0)] patients compared to controls [32.3 pg/mg creatinine (10th-90th percentiles: 21.8-58.8)]. LTE(4) levels were higher (P < 0.001) in patients with active disease than in patients in remission, for whom the levels of LTE(4) were similar to the levels of controls. Cysteinyl leukotriene pathway activation could contribute to the inflammation associated with IBD. The quantification of urinary LTE(4) could be an interesting noninvasive biomarker for the assessment of IBD activity.


Analysis of morphological parameters in pelvic radiography and hip MRI : a practical reporting recommendation.
Although numerous criteria have been proposed to define abnormal hip morphology, mostly used in the diagnosis of femoroacetabular impingement, it is not a practical approach to measure all of these parameters in all cases without clinical suspicion. In this study, our aim was to develop an evaluating and reporting standardization for routine hip examinations to define both hip morphology and impingement. A total of 108 patients with routine hip magnetic resonance imaging (MRI) and antero-posterior pelvic radiograph (PR) were included in this retrospective study. Alpha angle (AA), acetabular depth (AD), acetabular protrusion, acetabular anteversion, collo- diaphyseal angle (CDA), lateral center-edge angle (LCEA) and Tönnis angle (TA) were measured. The differences and associations between these parameters were evaluated according to imaging modality or plane, and sex. Although a significant difference has been found between the axial AA and the coronal AA mean values measured on MRI, there was also a strong correlation. Coronal measurements were significantly higher. AA values measured in PR and coronal MRI were comparable. Males had higher AA in both planes as compared to females. There were no significant differences between CDA values in MRI and PR. There was a significant difference and a moderate correlation between AD values in MRI and PR. We suggest that routine reports should include a measurement of AA in two planes, and measurement of CDA in PR or MRI. Due to the difference in AD between MRI and radiography, LCEA or TA may represent better alternatives. Checking for a negative Tönnis sign would represent a practical approach.


Nutritional status and dietary manipulation in predialysis chronic renal failure patients.
A properly implemented dietary treatment for patients with chronic renal failure (CRF) can correct several metabolic and endocrine disturbances and delay initiation of dialysis, but concerns exist about the risk of malnutrition and protein depletion. The goal of this study is to evaluate nutritional status and its relation to the dietary treatment in patients with advanced CRF. Cross-sectional survey. Predialysis outpatient clinic. Seventy patients (43 males, 27 females, 50 +/- 12 years) with severe CRF (glomerular filtration rate [GFR] <15 mL/min) being treated with a low-protein (0.6 g/kg/day) diet (LPD) or a very-low-protein (0.3 g/kg/day) diet supplemented with essential amino acids and ketoacids (KAD). Fifty-two healthy subjects with comparable age and sex served as controls. In all patients and controls, we performed biochemistry, anthropometry, bioelectrical impedance vector analysis (BIVA), and subjective global assessment (SGA), and the patients' outcomes were also assessed. Values of anthropometry and BIVA were similar in patients and controls. SGA scores showed a normal nutritional status (SGA-0) in 50 patients (71.4%) and mild to moderate SGA abnormalities (SGA-1) in 20 patients (28.6%); none had severe malnutrition. The SGA-1 patients differed from the SGA-0 patients by having higher serum urea, lower bicarbonate, and lower renal function (87% of SGA-1 patients had GFR <10 mL/min.). At the same GFR values (6.6 +/- 2.3 versus 6.6 +/- 2.3 mL/min) SGA-1 patients had lower bicarbonate (21.9 +/- 4.3 versus 25.3 +/- 2.7 mM, P <.01) and higher serum urea (115 +/- 29 versus 82 +/- 38 mg/dL, P =.01) and protein intake than SGA-0 patients; SGA-1 score was more prevalent with LPD compared with KAD treatment (45% versus 27%, P <.05). BIVA and anthropometry, serum levels of albumin, prealbumin, insulin-like growth factor-1, hematocrit, and lymphocyte count did not differ between SGA-1 and SGA-0 patients, but the number entering dialysis was higher in the group scoring as SGA-1 compared with SGA-0 (82% versus 47%, P <.05). With a planned dietary regimen, severe or overt malnutrition does not occur in predialysis CRF without other serious illnesses. However, some mild to moderate SGA abnormalities were detected in association with a more severe renal insufficiency, a lower serum bicarbonate, a higher serum urea and dietary protein levels and were predictive of poor renal outcome. This study emphasizes the role of proper dietary implementation, correction of metabolic acidosis, and clinical monitoring including SGA in the predialysis conservative care of CRF patients.


Factors affecting continuity and success of community-based reproductive health service programme in rural community of Northeast Ethiopia.
To assess opportunities and threats towards the continuity and success of Community based reproductive health service programme in Northeast Ethiopia. Community based comparative cross sectional study. Two districts of Amhara region, Ethiopia, classified as strong and weak community based reproductive health programme areas. Seven hundred and ninety two women aged 15-49 years residing in the selected districts of Amhara region. Community based reproductive health workers, programme coordinators and field supervisors were used as informants of qualitative data collection. Current use of modern contraceptive methods. Strong versus weak programme areas: knowledge about modern contraceptive method (MCM), was (90% and 86.8%), [OR (95% CI) = 2.87(1.68,4.91)], ever use of MCM (61.1% and 29.7%), [OR (95% CI) = 3.71(2.72, 5.07)] and current use of MCM (54.8% versus 19.7%), [OR (95% CI) = 4.95(3.53,6.95)]. Method interruption was significantly higher, 37.6% in weak than 10.9% in strongly performing programme area. Causes of defaulting in strong versus weak programme areas were: wanted more pregnancy (4% and 39.5%), fear of contraceptives' side effects (16% and 31.6%) and lack of method of choice (20% and 2.6%). Type of religion, husband approval, awareness of service existence and client satisfaction remained to be the predictors of current use of MCM in multivariate analysis. Qualitative study findings were found coherent with the quantitative results. Type of religion, husband approval, client satisfaction and awareness of service existence were the predictors of modern contraceptive methods utilisation in the study population.


Correlation of (18)F-fluoroethyl tyrosine positron-emission tomography uptake values and histomorphological findings by stereotactic serial biopsy in newly diagnosed brain tumors using a refined software tool.
Magnetic resonance imaging (MRI) is the standard neuroimaging method to diagnose neoplastic brain lesions, as well as to perform stereotactic biopsy surgical planning. MRI has the advantage of providing structural anatomical details with high sensitivity, though histological specificity is limited. Although combining MRI with other imaging modalities, such as positron-emission tomography (PET), has proven to increment specificity, exact correlation between PET threshold uptake ratios (URs) and histological diagnosis and grading has not yet been described. The aim of this study was to correlate exactly the histopathological criteria of the biopsy site to its PET uptake value with high spatial resolution (mm(3)), and to analyze the diagnostic value of PET using the amino acid O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) PET in patients with newly diagnosed brain lesions in comparison to histological findings obtained from stereotactic serial biopsy. A total of 23 adult patients with newly diagnosed brain tumors on MRI were enrolled in this study. Subsequently to diagnoses, all patients underwent a (18)F-FET PET-guided stereotactic biopsy, using an original newly developed software module, which is presented here. Conventional MRI, stereotactic computed tomography series, and (18)F-FET PET images were semiautomatically fused, and hot-spot detection was performed for target planning. UR was determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR values ≥1.6 were considered positive for glioma. High-grade glioma (HGG) was suspected with URs ≥3.0, while low-grade glioma (LGG) was suspected with URs between 1.6 and 3.0. Stereotactic serial biopsies along the trajectory at multiple sites were performed in millimeter steps, and the FET URs for each site were correlated exactly with a panel of 27 different histopathological markers. Comparisons between FET URs along the biopsy trajectories and the histological diagnoses were made with Pearson product-moment correlation coefficients. Analysis of variance was performed to test for significant differences in maximum UR between different tumor grades. A total of 363 biopsy specimens were taken from 23 patients by stereotactic serial biopsies. Histological examination revealed eight patients (35%) with an LGG: one with a World Health Organization (WHO)-I lesion and seven with a WHO-II lesion. Thirteen (57%) patients revealed an HGG (two with a WHO-III and three with a WHO-IV tumor), and two patients (9%) showed a process that was neither HGG nor LGG (group X or no-grade group). The correlation matrix between histological findings and the UR revealed five strong correlations. Low cell density in tissue samples was found to have a significant negative correlation with the measured cortical uptake rate (r=-0.43, P=0.02), as well as moderate cell density (r=-0.48, P=0.02). Pathological patterns of proliferation (r=0.37, P=0.04), GFAP (r=0.37, P=0.04), and Olig2 (r=0.36, P=0.05) showed a significant positive correlation with cortical URs. Analysis of variance tests showed a significant difference between the LGG and the HGG groups (F=8.27, P<0.002), but no significant differences when differentiating between the X group and the HGG (P=0.2)/LGG (P=0.8) groups, nor between the no-grade group and the WHO-I group. (18)F-FET PET is a valuable tool, as it allows the differentiation of HGGs from LGGs. Its use is not limited to preoperative evaluation; it may also refine biopsy targeting and improve tumor delimitation for radiotherapy. Histology is still necessary, and remains the gold standard for definitive diagnosis of brain lesions.


Music for the injured soldier: a contribution of American women's military bands during World War II.
This study is an investigation of the contributions of women's military bands in the United States to the reconditioning of the injured American troops during World War II. Primary and secondary sources revealed that these bands welcomed home hospital ships, performed for convalescing soldiers in hospitals, and provided music for hospital dances. While each of the bands investigated served in similar capacities, only one, the 403rd Women's Army Corps (WAC) Band, was stationed at a hospital. While entertainment by women's bands was an important part of the Army Reconditioning Program for the injured, the study also revealed a working partnership that developed between these musicians and the medical community. Sixty years after the war, band members believe their performances in hospitals were the most important contribution of their service. Some historians have concluded that music used in military hospitals during the war was the impetus for the music therapy profession.


A reinforcement discrete neuro-adaptive control for unknown piezoelectric actuator systems with dominant hysteresis.
The theoretical and experimental studies of a reinforcement discrete neuro-adaptive control for unknown piezoelectric actuator systems with dominant hysteresis are presented. Two separate nonlinear gains, together with an unknown linear dynamical system, construct the nonlinear model (NM) of the piezoelectric actuator systems. A nonlinear inverse control (NIC) according to the learned NM is then designed to compensate the hysteretic phenomenon and to track the reference input without the risk of discontinuous response. Because the uncertainties are dynamic, a recurrent neural network (RNN) with residue compensation is employed to model them in a compact subset. Then, a discrete neuro-adaptive sliding-mode control (DNASMC) is designed to enhance the system performance. The stability of the overall system is verified by Lyapunov stability theory. Comparative experiments for various control schemes are also given to confirm the validity of the proposed control.


Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis.
Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background. Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage (3)H-cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice. The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis.