Posttraumatic Stress Disorder in Patients with Heavy Alcohol Consumption and Alcoholic Hepatitis.
Lifetime prevalence of posttraumatic stress disorder (PTSD) in the general population is reported to be 6.8%. Individuals with alcohol dependence and substance abuse have high prevalence of PTSD. However, the prevalence of PTSD in heavy drinkers with alcoholic hepatitis (AH) is not known.The study's aim was to determine the prevalence of PTSD in heavy drinkers with and without AH. We screened for PTSD using the Primary Care-PTSD questionnaire among heavy drinkers with (n = 115) and without (n = 64) AH participating in a multicenter observational study in which participants were followed up to 12 months following their enrollment. The prevalence of PTSD in heavy drinkers with AH was 34% and was not different from heavy drinking controls without liver disease (34%). In the entire group screened for PTSD, the presence of PTSD was associated with higher alcohol consumption as reported by average drinks per last 30 days and average grams of alcohol consumed per day (p = 0.047 for both tests), but not associated with relapse of heavy drinking or mortality. Similarly, patients with AH and PTSD did not have higher relapse rate or higher mortality compared to patients with AH but no PTSD. Compared to previously reported prevalence in general population, heavy drinking individuals with or without AH have significantly higher prevalence of PTSD. However, PTSD was not associated with higher relapse rate or higher mortality in this population.


Computerized videodefecography versus defecography: do we need radiographs?
Defecography has been recognized as a valuable method for evaluating patients with evacuation disorders. It consists of the use of static radiography and fluoroscopy to record different situations within anorectal dynamics. Conventionally, rectal parameters are measured using radiograms. It is rare for fluoroscopy alone to be used. Computer software has been developed with the specific aim of calculating these measurements from digitized videotaped images obtained during fluoroscopy, without the need for radiographic film, thereby developing a computerized videodefecography method. The objective was thus to compare measurements obtained via computerized videodefecography with conventional measurements and to discuss the advantages of the new method. Prospective study at the radiology service of Hospital das Clínicas, Universidade de São Paulo. Ten consecutive normal subjects underwent videodefecography. The anorectal angle, anorectal junction, puborectalis muscle length, anal canal length and degree of anal relaxation were obtained via the conventional method (using radiography film) and via computerized videodefecography using the ANGDIST software. Measurement and analysis of these parameters was performed by two independent physicians. Statistical analysis confirmed that the measurements obtained through direct radiography film assessment and using digital image analysis (computerized videodefecography) were equivalent. Computerized videodefecography is equivalent to the traditional defecography examination. It has the advantage of offering reduced radiation exposure through saving on the use of radiography.


Co-amplification of the HER2 gene and chromosome 17 centromere: a potential diagnostic pitfall in HER2 testing in breast cancer.
Co-amplification of the centromere on chromosome 17 (CEP17) and HER2 can occur in breast cancer. Such aberrant patterns (clusters) on CEP17 can be misleading to calculate the HER2/CEP17 ratio, and thus underreporting of HER2 amplification. We identified 14 breast cancers retrospectively with HER2/CEP17 co-amplification and performed FISH (fluorescence in situ hybridization) with additional chromosome 17 probes (17p11.1-q11.1, 17p11.2-p12, TP53 on 17p13.1, RARA on 17q21.1-3 and TOP2 on 17q21.3-22) to characterize the spanning of the amplicon in these cases. Furthermore, the HER2 status was analyzed by means of HER2 silver in situ hybridization (SISH) and immunohistochemistry (IHC). The co-amplification of HER2/CEP17 was compared between the three institutions. TP53 was eusomic in all cases, 17p11.2-p12 in 79% (11/14), whereas 17p11.1-q11.1 showed chromosomal gain in all cases. RARA was amplified in 10/14 cases (71%) and TOP2 in 3/14 cases (21%). HER2 was amplified with FISH/SISH in all 14 cases. 9/14 tumors were 3+ IHC positive (64%) and 3 cases were 2+ IHC positive. In our cohort the CEP17 amplicon almost always involves the HER2 but not the TOP2 locus. Overall agreement on HER2/CEP17 ratio (when applying ASCO/CAP guidelines) was only 64% (9/14 cases) between the institutions. Discrepant ratios varied from 1.1 to 14.3. The HER2/CEP17 co-amplification is not defined in the ASCO/CAP guidelines, and may result in inaccurate HER2-FISH/SISH status, particularly if only the calculated HER2/CEP17 ratio is reported. It is recommended to report separate CEP17 and HER2 signals in complex HER2/CEP17 patterns.


Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.
This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.


Social representation and practices related to dementia in Hai District of Tanzania.
With the increasing number of people surviving into old age in Africa, dementia is becoming an important public health problem. Understanding the social dynamics of dementia in resource-poor settings is critical for developing effective interventions. We explored the socio-cultural beliefs surrounding dementia and the life experience of people with dementia (PWD) and their caregivers in the Hai District of Kilimanjaro, Tanzania. Cross-sectional qualitative design. Forty one PWD were purposively sampled from the Hai District of Kilimanjaro. Twenty five paired interviews with PWD and with caregivers, and 16 with caregivers alone, were conducted. Interviews were tape recorded, transcribed verbatim and analyzed using content analysis approach. Forty one PWD (26 females), aged 70 years and older, were recruited but due to speech difficulties only 25 participated in the interviews. Married were 13, widow in 22 and widower 6. The majority, 33/41 were illiterate. PWD and carers perceived memory problems as a normal part of ageing. Dementia was commonly referred as "ugonjwa wa uzeeni" (disease of old people) or memory loss disease. The majority of PWD 13/12 and carers 7/16 did not know what dementia is or what causes it. Dementia was felt to be associated with stroke, high blood pressure, diabetes, old age, curse/witchcraft and life stress. Half of the participants had used modern care and alternative care such as herbs, prayers or traditional healers. Caregivers complained about the burden of caring for PWD and suggested that community organizations should be involved in addressing the problem. Knowledge about dementia is low and the symptoms are accepted as a problem of old age. PWD and carers demonstrate pluralistic behaviour in seeking help from modern care, prayers and traditional healers. The disease adds significant burden to family members. Family and caregivers need more education on early recognition of symptoms and cost effective management of dementia at family level. Faith-based organizations could play an important role in dementia interventions. At a national level effective policy and improvement of the health care system to address the needs of PWD and their families are imperative.


Resonant bending of silicon nanowires by incident light.
Coupling of two dielectric wires with a rectangular cross section gives rise to bonding and anti-bonding resonances. The latter is featured by extremal narrowing of the resonant width for variation of the aspect ratio of the cross section and distance between wires. A plane wave resonant to this anti-bonding resonance gives rise to unprecedent enhancement of the optical forces up to several nano Newtons per micrometer length of the wires. The forces oscillate with the angle of incidence of the plane wave but always try to repel the wires. If the wires are fixed at the ends, the light power 1.5mW/µm2 bends wires with length 50 µm by order 100 nm.


Multidrug efflux pumps: structure, function and regulation.
Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities.


Tolerability and performance of BIP endotracheal tubes with noble metal alloy coating--a randomized clinical evaluation study.
Hospital acquired infections worsen the outcome of patients treated in intensive care units and are costly. Coatings with silver or metal alloys may reduce or alter the formation of biofilm on invasive medical devices. An endotracheal tube (ETT) is used to connect the patient to a ventilator and coated tubes have been tested in relation to bacterial colonization and respiratory infection. In the present study, we aimed to evaluate and compare a coated and uncoated ETT for patient symptoms and local tracheal tolerability during short term clinical use. Degree of bacterial colonization was also described. A silver-palladium-gold alloy coating ('Bactiguard®'Infection Protection, BIP) has been extensively used on urinary tract catheters and lately also on central venous catheters. We performed a randomised, single-blinded, controlled, first in man, post Conformité Européenne (EC) certification and CE marking study, focused on Bactiguard® coated ETTs (BIP ETT). Thirty patients at a tertiary university hospital scheduled for upper abdominal elective surgery with an expected duration of anaesthesia of at least 3 h were randomised; BIP ETT (n = 20) or standard ETT (n = 10). The tolerability was assessed with a modified version of Quality of Life Head and Neck Module, QLQ-H&N35 and by inspection of the tracheal mucosa with a fibre-optic bronchoscope before intubation and at extubation. Adverse Events (AE) and bacterial adherence were also studied. Statistical evaluations were carried out with the Fisher's Exact Test, the Clopper-Pearson method, as well as a Proportional Odds Model. Differences between groups were identified in 2 of 8 patient related symptoms with regard to tolerability by QLQ-H&N35 (cough, p = 0.022 and dry mouth, p = 0.014 in the treatment group.). No mucosal damage was identified with bronchoscopy. A low level of bacterial colonization with normal flora, equal between groups, was seen after short-term of intubation (median 5 h). No serious Adverse Events related to the use of an ETT were observed. The results should be treated with caution due to statistical confounders, a small study size and large inter-individual variability in bacterial adhesion. The new device BIP ETT is well tolerated and has good clinical performance during short-term intubation. Studies with larger sample sizes and longer intubation periods (>24 h) in the ICU-setting are needed and can now be planned in order to identify possible differences in clinical outcomes. Registered in ClinicalTrials.gov, NCT01682486 , Date of Registration: August, 30, 2012.


A community-based motivational personalised lifestyle intervention to reduce BMI in obese adolescents: results from the Healthy Eating and Lifestyle Programme (HELP) randomised controlled trial.
Approximately 7% of children and young people aged 5-15 years in the UK have obesity at a level likely to be associated with comorbidities. The majority of multicomponent lifestyle programmes have limited applicability and generalisability for British adolescents.The Healthy Eating and Lifestyle Programme (HELP) was a specific adolescent-focused intervention, designed for obese 12 to 18-year-olds seeking help to manage their weight. Participants were randomised to the 12-session HELP intervention or standard care. The primary outcome was difference in mean body mass index (BMI) (kg/m2) between groups at week 26 adjusted for baseline BMI, age and sex. 174 subjects were randomised (87 in each arm), of whom 145 (83%) provided primary outcome data at week 26. At week 26 there were no significant effects of the intervention on BMI (mean change in BMI 0.18 kg/m2 for the intervention arm, 0.25 kg/m2 for the control arm; adjusted difference between groups: -0.11 kg/m2 (95% CI -0.62 to 0.40), p=0.7). At weeks 26 and 52 there were no significant differences between groups in any secondary outcomes. At minimum this study reinforces the need for higher level, structured interventions to tackle the growing public health burden of obesity in the UK and internationally.The HELP intervention was no more effective than a single educational session for reducing BMI in a community sample of obese adolescents.Further work is needed to understand how weight management programmes can be delivered effectively to young people from diverse and deprived backgrounds in which childhood obesity is common. The study has significant implications in terms of informing public health interventions to tackle childhood obesity. ISRCTN: ISRCTN99840111.


Delayed diagnosis and treatment of high grade blunt pancreatic trauma. Case report and review of literature.
Despite technological advancement, high grade pancreatic injuries following blunt abdominal trauma continues to remain a disease that is associated with high morbidity and mortality rates, particularly in cases of delayed diagnosis. The aim of this paper was the presentation of delayed diagnosis and treatment peculiarities of high grade pancreatic trauma and a review of literature. A 55-years old man, involved in motor vehicle crashes, was referred to our level I trauma center. Hemodynamically stable. Abdominal physical exam, laboratory and focused abdominal sonography for trauma were normal. First total body multidetector CT scan, performed only after 24 hours, showed almost complete left pneumothorax, left third to fifth rib fractures and subcutaneous emphysema. Left chest tube was applied. On the eighth post-traumatic day, the general condition of the patient started to deteriorate. The patient showed abdominal pain, fever, nausea, vomiting, and bilateral flank ecchymosis. Only the third CT scan performed, on twelfth day, after the peritoneal signs, changes in blood and biochemical parameters appear, we revealed linear laceration and hypo-attenuation area of the neck and a part of distal body pancreas. In laparotomy fat necrosis, giant retroperitoneal abscess, necrosis of the neck and distal body of the pancreas, was found. Distal pancreatectomy with splenectomy was performed. Postoperative course with extensive wound infection and necrotic leakage from peripancreatic drain was complicated. The patient was discharged two months after his operation without any events. On time diagnosis of pancreatic trauma, especially in polytrauma patients, continues to remain a challenge for trauma surgeons. Main pancreatic duct injury is an important prognostic factor and the major one determining therapeutic approaches. Adequate surgical approaches decrease morbidity and mortality in pancreatic trauma. Delayed diagnosis, Distal pancreatectomy, Pancreatic blunt trauma.


Intelligence and Fetal Alcohol Spectrum Disorders: A Review.
Background: The studies on intelligence in individuals with fetal alcohol exposure are conflicting. Some have found a relevant impairment in this population, while others found results that were consistent with the population at large. Describe the results of studies on intelligence in individuals with Fetal Alcohol Spectrum Disorders. Indexed articles of the last 10 years were selected for an integrative literature review. After inclusion and exclusion criteria were satisfied 37 articles were selected. General intelligence, both verbal and non-verbal, is impaired in people who are prenatally exposed to alcohol. There is a tendency to a greater reduction in the Freedom from Distractibility/Working Memory Index of Wechsler Scales. Reduction in intelligence seems to occur on a continuum similar to the fetal alcohol spectrum. The reduction of the Freedom from Distractibility/Working Memory Index appears to be a reflection of a greater impairment of mathematical ability.


Accuracy of predicting the genetic risk of disease using a genome-wide approach.
The prediction of the genetic disease risk of an individual is a powerful public health tool. While predicting risk has been successful in diseases which follow simple Mendelian inheritance, it has proven challenging in complex diseases for which a large number of loci contribute to the genetic variance. The large numbers of single nucleotide polymorphisms now available provide new opportunities for predicting genetic risk of complex diseases with high accuracy. We have derived simple deterministic formulae to predict the accuracy of predicted genetic risk from population or case control studies using a genome-wide approach and assuming a dichotomous disease phenotype with an underlying continuous liability. We show that the prediction equations are special cases of the more general problem of predicting the accuracy of estimates of genetic values of a continuous phenotype. Our predictive equations are responsive to all parameters that affect accuracy and they are independent of allele frequency and effect distributions. Deterministic prediction errors when tested by simulation were generally small. The common link among the expressions for accuracy is that they are best summarized as the product of the ratio of number of phenotypic records per number of risk loci and the observed heritability. This study advances the understanding of the relative power of case control and population studies of disease. The predictions represent an upper bound of accuracy which may be achievable with improved effect estimation methods. The formulae derived will help researchers determine an appropriate sample size to attain a certain accuracy when predicting genetic risk.


Stress correlations in granular materials: an entropic formulation.
We study the response of dry granular materials to external stress using experiment, simulation, and theory. We derive a Ginzburg-Landau functional that enforces mechanical stability and positivity of contact forces. In this framework, the elastic moduli depend only on the applied stress. A combination of this feature and the positivity constraint leads to stress correlations whose shape and magnitude are extremely sensitive to the nature of the applied stress. The predictions from the theory describe the stress correlations for both simulations and experiments semiquantitatively.


Risk factors for post-traumatic stress disorder among UK Armed Forces personnel.
There is considerable interest in understanding further the factors that increase the risk of post-traumatic stress disorder (PTSD) for military personnel. This study aimed to investigate the relative contribution of demographic variables; childhood adversity; the nature of exposure to traumatic events during deployment; appraisal of these experiences; and home-coming experiences in relation to the prevalence of PTSD 'caseness' as measured by a score of 50 on the PTSD Checklist (PCL) in UK Armed Forces personnel who have been deployed in Iraq since 2003. Data were drawn from the first stage of a retrospective cohort study comparing UK military personnel who were deployed to the 2003 Iraq War with personnel serving in the UK Armed Forces on 31 March 2003 but who were not deployed to the initial phase of war fighting. Participants were randomly selected and invited to participate. The response rate was 61%. We have limited these analyses to 4762 regular service individuals who responded to the survey and who have been deployed in Iraq since 2003. Post-traumatic stress symptoms were associated with lower rank, being unmarried, having low educational attainment and a history of childhood adversity. Exposure to potentially traumatizing events, in particular being deployed to a 'forward' area in close contact with the enemy, was associated with post-traumatic stress symptoms. Appraisals of the experience as involving threat to one's own life and a perception that work in theatre was above an individual's trade and experience were strongly associated with post-traumatic stress symptoms. Low morale and poor social support within the unit and non-receipt of a home-coming brief (psycho-education) were associated with greater risk of post-traumatic stress symptoms. Personal appraisal of threat to life during the trauma emerged as the most important predictor of post-traumatic stress symptoms. These results also raise the possibility that there are important modifiable occupational factors such as unit morale, leadership, preparing combatants for their role in theatre which may influence an individual's risk of post-traumatic stress symptoms. Therefore interventions focused on systematic preparation of personnel for the extreme stress of combat may help to lessen the psychological impact of deployment.


The Effects of a Nematode Lungworm (Rhabdias hylae) on its Natural and Invasive Anuran Hosts.
Biological invasions can bring both the invader and native taxa into contact with novel parasites. As cane toads ( Rhinella marina ) have spread through Australia, they have encountered lungworms (Rhabdias hylae) that occur in native frogs. Field surveys suggest that these lungworms have not host-switched to toads. In our laboratory studies, R. hylae infected cane toads as readily as it infected native frogs, but failed to reach the lungs of the novel host (i.e., were killed by the toads' immune response). Plausibly, then, R. hylae might reduce the viability both of their native hosts (frogs, that can exhibit high parasite burdens) and cane toads (that must deal with infective larvae traveling through the host body). Our laboratory trials suggest, however, that the impacts of the parasite on infected anuran hosts (both frogs and toads) were minimal, with no significant decrements to host survival, activity, growth, or locomotor performance. Ironically, the lack of impact of the parasite on its native hosts appears to be an outcome of co-evolution (frogs tolerate the lungworm), whereas the lack of impact on the novel host is due to a lack of co-evolution (toads can recognize and eliminate the lungworm).


High frequency of silver resistance genes in invasive isolates of Enterobacter and Klebsiella species.
Silver-based products have been marketed as an alternative to antibiotics, and their consumption has increased. Bacteria may, however, develop resistance to silver. To study the presence of genes encoding silver resistance (silE, silP, silS) over time in three clinically important Enterobacteriaceae genera. Using polymerase chain reaction (PCR), 752 bloodstream isolates from the years 1990-2010 were investigated. Age, gender, and ward of patients were registered, and the susceptibility to antibiotics and silver nitrate was tested. Clonality and single nucleotide polymorphism were assessed with repetitive element sequence-based PCR, multi-locus sequence typing, and whole-genome sequencing. Genes encoding silver resistance were detected most frequently in Enterobacter spp. (48%), followed by Klebsiella spp. (41%) and Escherichia coli 4%. Phenotypical resistance to silver nitrate was found in Enterobacter (13%) and Klebsiella (3%) isolates. The lowest carriage rate of sil genes was observed in blood isolates from the neonatology ward (24%), and the highest in blood isolates from the oncology/haematology wards (66%). Presence of sil genes was observed in international high-risk clones. Sequences of the sil and pco clusters indicated that a single mutational event in the silS gene could have caused the phenotypic resistance. Despite a restricted consumption of silver-based products in Swedish health care, silver resistance genes are widely represented in clinical isolates of Enterobacter and Klebsiella species. To avoid further selection and spread of silver-resistant bacteria with a high potential for healthcare-associated infections, the use of silver-based products needs to be controlled and the silver resistance monitored.


Detection of three human adenovirus species in adults with acute respiratory infection in China.
Human adenoviruses (HAdVs) are recognized as causal agents in a wide range of human diseases. However, researchers lack sufficient data on the exact HAdV species and serotypes associated with adult acute respiratory tract infections (ARTIs). To detect and characterize HAdV infections in adults in China, clinical specimens were collected from 10,310 adults with ARTIs from May 2005 to July 2010. The partial HAdV hexon gene was amplified by polymerase chain reaction (PCR), sequenced, and phylogenetically analyzed. HAdVs were detected in 86 samples (0.8%), of which 67 (77.9%) were species B (HAdV-3, -7, -11, and -14), 7 (8.1%) were species C (HAdV-1, -2, and -6), and 12 (14%) were species E (HAdV-4). HAdV-3 was the most frequently detected serotype (41/86, 47.7%), followed by HAdV-7 (13/86, 15.1%), HAdV-4 (12/86, 14.0%), and HAdV-11 (11/86, 12.8%). Patients 14-25 years old (60.5%) exhibited a higher rate of adenovirus detection than older patients. Co-infections with other respiratory viruses were observed in samples positive for HAdV species B and E. Human rhinovirus was the most commonly found virus in patients with HAdV infection. These findings provide baseline data for the surveillance and control of HAdV infection in China.


Panic disorder in otoneurological experience.
The evaluation of cochleovestibular dysfunction in psychiatric patients often causes a difficult problem in neurootological experience. The authors discuss here the neurobiological basis of panic disorders and cochleovestibular dysfunction. In this multicenter study, we examined 63 patients with vertigo and panic disease. Twenty patients with primary panic disease and consecutive vertigo composed group 1, whereas group 2 comprised 43 vertiginous patients with secondary panic disease. The most interesting question is whether the patients have an organic vestibular lesion, which would explain why vertigo alone is the problematic symptom in these panic patients, whereas in other patients, panic disease can cause other severe symptoms that resemble heart attack, dyspnea, or abdominal crisis. Vertigo has a bidirectional connection with psychiatric disorders. The panic disorder can be superimposed on chronic vertigo, and psychiatric patients with a cochleovestibular lesion have diminished chances for complete recovery. The examination of psychiatric patients with vertigo is very time consuming and requires much more empathy than does examination of vertiginous patients with a normal mental state. Anxiety provokes somatic and behavioral symptoms in most such patients. The treatment of vertigo in panic patients and of the panic disorder in vertiginous patients requires cooperation between neurootologist and psychiatrist.


Targeting autophagic pathways for cancer drug discovery.
Autophagy, an evolutionarily conserved lysosomal degradation process, has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.


Cadmium accumulation in the human retina: effects of age, gender, and cellular toxicity.
Tobacco smoking and aging are among the few factors linked to age-related macular degeneration (AMD), a major cause of blindness in the elderly. Recent studies indicate that cadmium (Cd), an environmental toxic trace metal, is approximately four-fold higher in the retinas of smokers compared to non-smokers. In this study, we determined the effects of age and gender on Cd accumulation in human retinal tissues, specifically the neural retina, retinal pigment epithelium (RPE), and choroid. Cadmium levels in cultured RPE cells or retinal tissues isolated from frozen donor eyes were measured using inductively coupled plasma mass spectrometry (ICP-MS) and graphite furnace atomic absorption spectrophotometry (GF-AAS). Cadmium uptake in cultured human RPE cells (ARPE-19) was also assessed using GF-AAS. Toxic effects of cadmium were determined from cell loss (measured as a decrease in cell density) and lactate dehydrogenase release (an indicator of membrane disruption). In "young" eyes (< 55 years) Cd was highest in the retinal pigment epithelium and lowest in the neural retina. Cd was higher in all tissues in aged eyes (>or=55 years) and was significantly higher in the neural retina and RPE in older females. Cultured RPE cells exposed to Cd showed altered cell morphology, decreased cell survival, elevated ROS levels and concentration-dependent disruption of membrane integrity. We conclude that cadmium is accumulated differently in the neural retinal and RPE of older men and women. The deleterious effects of Cd on RPE cells indicate that this environmental toxin is a potentially important factor in age-related retinal disease.


Melanotic neuroectodermal tumor of infancy: clinical, radiologic, and pathologic findings in five cases.
Five pathologically proved melanotic neuroectodermal tumors of infancy are reported. These rare neoplasms of infancy exhibit a distinct predilection for the maxillary bone. Three tumors originated in the maxilla, one in the calvaria, and one in the cerebellar vermis. Those occurring in bone did not metastasize but were locally invasive, as reflected in their radiologic appearance. Bone erosion, expansion, hyperostosis, and osteogenesis can occur in the same neoplasm and were appreciated best on CT. MR imaging showed the soft-tissue component and extent of the neoplasm better than CT did. The pathologic findings from all five cases (and one possibly related melanotic tumor of the face) revealed abundant melanin. MR imaging of two melanotic tumors showed isointense T1-weighted and slightly hyperintense T2-weighted signals. This appearance is contrary to that of most melanin-containing tumors, which exhibit enhanced T1 and T2 relaxation, and indicates that variables other than the absolute amount of melanin may determine the MR signal. Clinically, rapid neoplastic growth and excessive melanin production by the tumor cells caused facial disfigurement and visible blue black discoloration. All five melanotic neuroectodermal tumors were resected and the vermian tumor was also irradiated. Four of five children were well and free from disease 1 month to 7 years after resection. The calvarial tumor was incompletely resected and involved the underlying brain, eventually causing death. The clinical, radiologic, and pathologic features of melanotic neuroectodermal tumors of infancy are reviewed. Melanotic neuroectodermal tumors of infancy that involve bone can be diagnosed from the clinical and radiologic findings. Prompt diagnosis and surgical resection are essential for cure.


Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.
Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively. In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.


Endocrinological correlates of male bimaturism in wild Bornean orangutans.
Among primates, orangutans are unique in having pronounced male bimaturism leading to two fully adult morphs that differ in both physical appearance and behavior. While unflanged males have a female-like appearance, flanged males have the full suite of secondary sexual characteristics, including cheek flanges and a large throat sac. So far, hormonal correlates of arrested development in unflanged males and the expression of secondary sexual characteristics in flanged males have only been studied in zoo-housed individuals. In this study, we investigated fecal androgen and glucocorticoid metabolites as hormonal correlates of male bimaturism in 17 wild adult Bornean orangutans (Pongo pygmaeus) in Central Kalimantan, Indonesia. We predicted and found higher androgen levels in flanged males compared to unflanged males, probably due to ongoing strong competition among flanged males who meet too infrequently to establish a clear linear dominance hierarchy. Furthermore, we found no difference in fecal glucocorticoid metabolite concentrations between flanged and unflanged males, indicating that social stress is unlikely to explain arrested development in unflanged wild orangutans. The only actively developing male in our study showed significantly higher androgen levels during the period of development than later as a fully flanged male. This supports earlier findings from zoo studies that elevated androgen levels are associated with the development of secondary sexual characteristics.


Consumer use and understanding of labelling information on edible marijuana products sold for recreational use in the states of Colorado and Washington.
In 2014, the states of Colorado and Washington began allowing retail sales of marijuana for recreational use. The regulatory agencies in these states have implemented specific labelling requirements for edible marijuana products sold for recreational use to help address concerns such as delayed activation time, accidental ingestion, and proper dosing. We conducted 12 focus groups with 94 adult consumers and nonconsumers of edibles in Denver and Seattle to collect information on their use and understanding of labelling information on edible marijuana products sold for recreational use. Specifically, we asked participants about the usefulness, attractiveness, ease of comprehension, relevancy, and acceptability of the label information. Some focus group participants look for and read specific information, such as the potency profile and serving size statement, but do not read or were unfamiliar with other labelling features. The focus groups revealed that participants have some concerns about the current labelling of edibles. In particular, participants were concerned that there is too much information on the labels so consumers may not read the label, there is no obvious indication that the product contains marijuana (e.g., a Universal Symbol), and the information on consumption advice is not clear. Participants in both locations suggested that education in a variety of formats, such as web- and video-based education, would be useful in informing consumers about the possible risks of edibles. The focus group findings suggest that improvements are needed in the labelling of edibles to prevent unintentional ingestion among adult nonusers and help ensure proper dosing and safe consumption among adult users. These findings, along with lessons learned from Colorado and Washington, can help inform the labelling of edibles as additional states allow the sale of edibles for recreational use.


Utility of psychological screening for the diagnosis of pediatric episodic vertigo.
Childhood episodic vertigo has been reported to be associated with migraine or childhood periodic syndromes such as benign paroxysmal vertigo of childhood. There is discrete evidence that unexpected recurrent vertigo is associated with a high level of depression and anxiety in adults. However, only a few studies describe the frequency and characteristics of psychiatric comorbidity in vertiginous children. The aim of this study is to evaluate the incidence and characteristics of emotional and behavioral problems using outpatient-based psychological screening tools in children with episodic vertigo attacks. A total of 105 patients and 138 controls, aged 4 to 17 years, were enrolled. All were identified with a primary complaint of recurrent episodic vertigo. All patients received a complete battery of audiological and vestibular tests. Psychological assessment was performed using standardized questionnaires, including Strength and Difficulties Questionnaire (SDQ), Children's Depression Inventory (CDI), and Screen for Child Anxiety Related Emotional Disorders (SCARED). Compared with community controls, children presenting vertigo attacks had significantly higher mean scores on almost all scales of SDQ, CDI, and SCARED, except two parameters, namely, prosocial behavior and separation anxiety. About half of the patients, compared to 10 to 11% of the controls, had significant levels of distress that could adversely impact treatment outcomes and might need psychiatric consultation. Significant distress or impairment in social interactions was more prominent in older ages. Our findings suggest that children/adolescents with recurrent episodic vertigo should be screened for possible associated psychological symptoms.


Prognostic accuracy of immunologic and metabolic markers for type 1 diabetes in a high-risk population: receiver operating characteristic analysis.
To establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study. A total of 339 subjects from the Diabetes Prevention Trial-Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers. Individually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70-0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively). The combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.


Time and place in the prehistory of the Aslian languages.
The Aslian language family, located in the Malay Peninsula and southern Thai Isthmus, consists of four distinct branches comprising some 18 languages. These languages predate the now dominant Malay and Thai. The speakers of Aslian languages exhibit some of the highest degree of phylogenetic and societal diversity present in Mainland Southeast Asia today, among them a foraging tradition particularly associated with locally ancient, Pleistocene genetic lineages. Little advance has been made in our understanding of the linguistic prehistory of this region or how such complexity arose. In this article we present a Bayesian phylogeographic analysis of a large sample of Aslian languages. An explicit geographic model of diffusion is combined with a cognate birth-word death model of lexical evolution to infer the location of the major events of Aslian cladogenesis. The resultant phylogenetic trees are calibrated against dates in the historical and archaeological record to infer a detailed picture of Aslian language history, addressing a number of outstanding questions, including (1) whether the root ancestor of Aslian was spoken in the Malay Peninsula, or whether the family had already divided before entry, and (2) the dynamics of the movement of Aslian languages across the peninsula, with a particular focus on its spread to the indigenous foragers.


Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations.
More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-γ ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.


Manuscript Architect: a Web application for scientific writing in virtual interdisciplinary groups.
Although scientific writing plays a central role in the communication of clinical research findings and consumes a significant amount of time from clinical researchers, few Web applications have been designed to systematically improve the writing process. This application had as its main objective the separation of the multiple tasks associated with scientific writing into smaller components. It was also aimed at providing a mechanism where sections of the manuscript (text blocks) could be assigned to different specialists. Manuscript Architect was built using Java language in conjunction with the classic lifecycle development method. The interface was designed for simplicity and economy of movements. Manuscripts are divided into multiple text blocks that can be assigned to different co-authors by the first author. Each text block contains notes to guide co-authors regarding the central focus of each text block, previous examples, and an additional field for translation when the initial text is written in a language different from the one used by the target journal. Usability was evaluated using formal usability tests and field observations. The application presented excellent usability and integration with the regular writing habits of experienced researchers. Workshops were developed to train novice researchers, presenting an accelerated learning curve. The application has been used in over 20 different scientific articles and grant proposals. The current version of Manuscript Architect has proven to be very useful in the writing of multiple scientific texts, suggesting that virtual writing by interdisciplinary groups is an effective manner of scientific writing when interdisciplinary work is required.


Osteoporosis of pregnancy.
Eight women with pregnancy-associated osteoporosis were studied for up to ten years. Back pain and vertebral collapse usually occurred in the first pregnancy and did not recur in two subsequent pregnancies. Except in one patient, bone histology showed no increase in resorption. Plasma concentrations of 1,25-dihydroxyvitamin D tended to be low whereas those of calcitonin were, with one exception, normal. It is suggested that in these patients there may have been a transient failure of the usual changes in calciotropic hormones to prepare the maternal skeleton for the stress of childbirth. However, subsequent pregnancies in such patients are not necessarily contraindicated.


Comparative Evaluation of Neem Mouthwash on Plaque and Gingivitis: A Double-blind Crossover Study.
The present study aimed at evaluating the impact of neem-containing mouthwash on plaque and gingivitis. This randomized, double-blinded, crossover clinical trial included 40 participants aged 18 to 35 years with washout period of 1 week between the crossover phases. A total of 20 participants, each randomly allocated into groups I and II, wherein in the first phase, group I was provided with 0.2% chlorhexidine gluconate and group II with 2% neem mouthwash. After the scores were recorded, 1-week time period was given to the participants to carry over the effects of the mouthwashes and then the second phase of the test was performed. The participants were instructed to use the other mouthwash through the second test phase. There was a slight reduction of plaque level in the first phase as well as in the second phase. When comparison was made between the groups, no statistically significant difference was seen. Both the groups showed reduction in the gingival index (GI) scores in the first phase, and there was a statistically significant difference in both groups at baseline and after intervention (0.005 and 0.01 respectively). In the second phase, GI scores were reduced in both groups, but there was a statistically significant difference between the groups only at baseline scores (0.01). In the present study, it has been concluded that neem mouthwash can be used as an alternative to chlorhexidine mouthwash based on the reduced scores in both the groups. Using neem mouthwash in maintaining oral hygiene might have a better impact in prevention as well as pervasiveness of oral diseases as it is cost-effective and easily available.


Differential rates of digestion of bacteria by freshwater and marine phagotrophic protozoa.
Differential decreases over time of two bacterial species, Escherichia coli and Enterococcus faecalis, in a freshwater and a marine ecosystem were observed and explained by a differential rate of digestion of these bacteria by phagotrophic flagellates and ciliates. For this purpose, fluorescence-labeled bacteria (FLB) were used and prepared from the two species cited above. The number of FLB was observed for 5 days in fresh and marine waters in the presence or absence (0.2-mum-pore-size-filtered water) of natural microbiota. These experiments showed a longer persistence of Enterococcus faecalis FLB as opposed to Escherichia coli FLB in the presence of natural microbiota. Removal of FLB was due to protozoan grazing because no decrease of FLB number was observed in the absence of natural microbiota. In short-term (about 40 min) ingestion experiments, we found similar clearance rates of Escherichia coli and Enterococcus faecalis FLB by assemblages of flagellates from the freshwater and the marine ecosystem and by cultured assemblages of ciliates from the marine ecosystem. Clearance rates of Enterococcus faecalis FLB were greater than those of Escherichia coli FLB for assemblages of ciliates from the freshwater ecosystem. Comparison of rates of ingestion and digestion of FLB by protozoa showed that Escherichia coli FLB were digested and ingested at similar rates. However, Enterococcus faecalis FLB were digested slower than they were ingested. These results suggest that a longer persistence of Enterococcus faecalis as opposed to Escherichia coli can be explained by a differential digestion by flagellates and ciliates in aquatic ecosystems. Moreover, rates of ingestion and digestion were strongly correlated for both FLB types.


Kinetic light scattering studies on the dissociation of hemoglobin from Lumbricus terrestris.
The kinetics of the pH-induced dissociation of the 3 X 10(6) mol wt hemoglobin from Lumbricus terrestris (the earthworm) have been studied in a light-scattering stopped-flow apparatus. The ligand dependent dissociation data were fit well by a simple sequential model. The data for CO and oxyhemoglobin are consistent with Hb12 leads to 2Hb6 leads to 12Hb. Methemoglobin at pH 7 appears to be hexameric and the dissociation is consistent with the model: Hb6 leads to 6Hb. In a sequential decay scheme for which light-scattering changes are monitored, the relative amounts of rapid and slow phase are determined by the rate constants as well as the molecular weights of intermediate species. Assignment of the hexameric intermediate is supported by an investigation of the sensitivity of the theoretical kinetic curves to the molecular weights of the intermediates. This assignment is further supported by the following: (1) the same model will fit the data for oxy- and CO-hemoglobin at all three temperatures (a 24-29-fold variation in rate constants), (2) evidence from electron microscopy shows hexameric forms, and (3) methemoglobin is apparently stable as a hexamer at pH 7. When CO replaces O2 as the ligand, the dissociation rate increases by a factor of four. The met is about 20 times faster than the initial oxyhemoglobin dissociation rate, but perhaps more relevant for comparing dissociation of the hexamer, the met rate was respectively 100 times and 500 times faster than that for the assumed hexameric forms of CO- and oxy-hemoglobin. The activation energies for the dodecamer to hexamer dissociation and for the dissociation of the hexamer to smaller forms were about 30 kcal/mol for oxy-, CO-, and methemoglobin.


Sinks for photosynthetic electron flow in green petioles and pedicels of Zantedeschia aethiopica: evidence for innately high photorespiration and cyclic electron flow rates.
A combination of gas exchange and various chlorophyll fluorescence measurements under varying O(2) and CO(2) partial pressures were used to characterize photosynthesis in green, stomata-bearing petioles of Zantedeschia aethiopica (calla lily) while corresponding leaves served as controls. Compared to leaves, petioles displayed considerably lower CO(2) assimilation rates, limited by both stomatal and mesophyll components. Further analysis of mesophyll limitations indicated lower carboxylating efficiencies and insufficient RuBP regeneration but almost similar rates of linear electron transport. Accordingly, higher oxygenation/carboxylation ratios were assumed for petioles and confirmed by experiments under non-photorespiratory conditions. Higher photorespiration rates in petioles were accompanied by higher cyclic electron flow around PSI, the latter being possibly linked to limitations in electron transport from intermediate electron carriers to end acceptors and low contents of PSI. Based on chlorophyll fluorescence methods, similar conclusions can be drawn for green pedicels, although gas exchange in these organs could not be applied due to their bulky size. Since our test plants were not subjected to stress we argue that higher photorespiration and cyclic electron flow rates are innate attributes of photosynthesis in stalks of calla lily. Active nitrogen metabolism may be inferred, while increased cyclic electron flow may provide the additional ATP required for the enhanced photorespiratory activity in petiole and pedicel chloroplasts and/or the decarboxylation of malate ascending from roots.


Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils.
The initial step in extravasation of neutrophils (polymorphonuclear leukocytes [PMNs]) to the extravascular space is adherence to the endothelium. We examined the effect of oxidants on this process by treating human endothelial cells with H2O2, t-butylhydroperoxide, or menadione. This resulted in a surface adhesive for PMN between 1 and 4 h after exposure. The oxidants needed to be present only for a brief period at the initiation of the assay. Adhesion was an endothelial cell-dependent process that did not require an active response from the PMN. The adhesive molecule was not platelet-activating factor, which mediates PMN adherence when endothelial cells are briefly exposed to higher concentrations of H2O2 (Lewis, M. S., R. E. Whatley, P. Cain, T. M. McIntyre, S. M. Prescott, and G. A. Zimmerman. 1988. J. Clin. Invest. 82:2045-2055), nor was it ELAM-1, an adhesive glycoprotein induced by cytokines. Oxidant-induced adhesion did not require protein synthesis, was inhibited by antioxidants, and, when peroxides were the oxidants, was inhibited by intracellular iron chelators. Granule membrane protein-140 (GMP-140) is a membrane-associated glycoprotein that can be translocated from its intracellular storage pool to the surface of endothelial cells where it acts as a ligand for PMN adhesion (Geng, J.-G., M. P. Bevilacqua, K. L. Moore, T. M. McIntyre, S. M. Prescott, J. M. Kim, G. A. Bliss, G. A. Zimmerman, and R. P. McEver. 1990. Nature (Lond). 343:757-760). We found that endothelial cells exposed to oxidants expressed GMP-140 on their surface, and that an mAb against GMP-140 or solubilized GMP-140 completely blocked PMN adherence to oxidant-treated endothelial cells. Thus, exposure of endothelial cells to oxygen radicals induces the prolonged expression of GMP-140 on the cell surface, which results in enhanced PMN adherence.


Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study.
To determine the skeletal safety and efficacy of long term (≥10 years) alendronate use in patients with osteoporosis. Open register based cohort study containing two nested case control studies. Nationwide study of population of Denmark. 61 990 men and women aged 50-94 at the start of treatment, who had not previously taken alendronate, 1996-2007. Treatment with alendronate. Incident fracture of the subtrochanteric femur or femoral shaft (ST/FS) or the hip. Non-fracture controls from the cohort were matched to fracture cases by sex, year of birth, and year of initiation of alendronate treatment. Conditional logistic regression models were fitted to calculate odds ratios with and without adjustment for comorbidity and comedications. Sensitivity analyses investigated subsequent treatment with other drugs for osteoporosis. 1428 participants sustained a ST/FS (incidence rate 3.4/1000 person years, 95% confidence interval 3.2 to 3.6), and 6784 sustained a hip fracture (16.2/1000 person years, 15.8 to 16.6). The risk of ST/FS was lower with high adherence to treatment with alendronate (medication possession ratio (MPR, a proxy for compliance) >80%) compared with poor adherence (MPR <50%; odds ratio 0.88, 0.77 to 0.99; P=0.05). Multivariable adjustment attenuated this association (adjusted odds ratio 0.88, 0.77 to 1.01; P=0.08). The risk was no higher in long term users (≥10 dose years; 0.70, 0.44 to 1.11; P=0.13) or in current compared with past users (0.91, 0.79 to 1.06; P=0.22). Similarly, MPR >80% was associated with a decreased risk of hip fracture (0.73, 0.68 to 0.78; P<0.001) as was longer term cumulative use for 5-10 dose years (0.74, 0.67 to 0.83; P<0.001) or ≥10 dose years (0.74, 0.56 to 0.97; P=0.03). These findings support an acceptable balance between benefit and risk with treatment with alendronate in terms of fracture outcomes, even for over 10 years of continuous use.


The key role of caregiver confidence in the caregiver's contribution to self-care in adults with heart failure.
Caregivers play an important role in contributing to heart failure (HF) patients' self-care but no prior studies have examined the caregivers' contributions to HF patients' self-care and no prior studies have examined potential determinants of the caregivers' contribution to HF patients' self-care. The purpose of this study was to describe the caregivers' contribution to HF patients' self-care and identify its determinants. The study design involved a secondary analysis of cross-sectional data. Caregivers' contributions were measured with the Caregiver's Contribution to Self-care of HF Index (CC-SCHFI) which measures the caregiver's contribution to self-care maintenance and management and caregiver confidence in contributing to HF patient's self-care. Potential determinants were measured using a socio-demographic questionnaire completed by caregivers and patients, and patient clinical data was obtained from the medical record. Data from 515 caregiver/patient dyads were analyzed. Most (55.5%) patients were male (mean age 75.6 years) and most (52.4%) caregivers were female (mean age, 56.6 years). The caregivers' contribution to patients' self-care maintenance was low in weight monitoring and physical activity but higher in checking ankles, advising on low-salt foods and taking medicines. The caregivers' contribution to patients' self-care management was low in symptom recognition. When symptoms were recognized, caregivers advised patients to reduce fluids and salt and call the provider but rarely advised to take an extra diuretic. Caregiver confidence in the ability to contribute to patient self-care explained a significant amount of variance in the caregiver's contribution. These findings suggest that caregivers in this sample did not contribute meaningfully to HF self-care. Providers should educate both HF patients and caregivers. Interventions that improve caregiver confidence have the potential to successfully increase the caregivers' contribution to patients' self-care.


Extending self-organizing particle systems to problem solving.
Self-organizing particle systems consist of numerous autonomous, purely reflexive agents ("particles") whose collective movements through space are determined primarily by local influences they exert upon one another. Inspired by biological phenomena (bird flocking, fish schooling, etc.), particle systems have been used not only for biological modeling, but also increasingly for applications requiring the simulation of collective movements such as computer-generated animation. In this research, we take some first steps in extending particle systems so that they not only move collectively, but also solve simple problems. This is done by giving the individual particles (agents) a rudimentary intelligence in the form of a very limited memory and a top-down, goal-directed control mechanism that, triggered by appropriate conditions, switches them between different behavioral states and thus different movement dynamics. Such enhanced particle systems are shown to be able to function effectively in performing simulated search-and-collect tasks. Further, computational experiments show that collectively moving agent teams are more effective than similar but independently moving ones in carrying out such tasks, and that agent teams of either type that split off members of the collective to protect previously acquired resources are most effective. This work shows that the reflexive agents of contemporary particle systems can readily be extended to support goal-directed problem solving while retaining their collective movement behaviors. These results may prove useful not only for future modeling of animal behavior, but also in computer animation, coordinated movement control in robotic teams, particle swarm optimization, and computer games.


Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action.
Parkinson's disease (PD) is a common, progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Numerous studies have provided evidence suggesting that neuroinflammation plays an important role in the pathogenesis of PD. In this study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether human mesenchymal stem cells (hMSCs) have a protective effect on the dopaminergic system through anti-inflammatory mechanisms. The hMSC treatment significantly decreased LPS-induced microglial activation, tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS) mRNA expression, and production of NO and TNF-alpha compared with the LPS-only treatment group. In co-cultures of microglia and mesencephalic dopaminergic neurons, hMSC treatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells. The hMSC treatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the SN was considerably decreased and was clearly accompanied by a decrease in activation of microglia, as well as TNF-alpha and iNOS mRNA expression and production of TNF-alpha. These data suggest that hMSCs have a neuroprotective effect on dopaminergic neurons through anti-inflammatory actions mediated by the modulation of microglial activation. Along with various trophic effects and trans-differentiational potency, the anti-inflammatory properties of MSCs could have major therapeutic implications in the treatment of PD.


In vivo optical imaging in arthritis--an enlightening future?
In vivo molecular optical imaging has significant potential to delineate and measure, at the macroscopic level, in vivo biological processes that are occurring at the cellular and molecular level. Optical imaging has already been developed for in vitro and ex vivo applications in molecular and cellular biology (e.g. fluorescence confocal microscopy), but is still at an early stage of development as a whole-animal in vivo imaging technique. Both sensitivity and spatial resolution remain incompletely defined. Rapid advances in hardware technology and highly innovative reporter probes and dyes will be expected to deliver significant insight into perturbations of molecular pathways that occur in disease, ultimately with the potential of translating into future molecular imaging techniques for patients with arthritis. This review will focus on currently available technologies for live in vivo animal optical imaging, including fluorescence reflectance imaging, potential novel tomographic techniques, bioluminescence reporter technology and potential novel labelling techniques, highlighting in particular the potential application of in vivo fluorescence imaging in arthritis.


Clinical and endocrinologic characterization of a patients with the syndrome of incomplete testicular feminization.
A 46 XY individual with male pseudohermaphroditism was investigated. The phenotype was distinctive in that the habitus was female in character, but partial fusion of the labioscrotal folds, testes, and male wolffian duct structures that terminated in the vagina were present. Müllerian structures were absent. At the expected time of puberty both feminization (breast development) and virilization (clitoral enlargement) took place. Studies of estrogen and androgen dynamics revealed plasma testosterone levels and production rates characteristic of normal men. Plasma estrogen levels and production rates were greater than those of normal men. Plasma gonadotropin levels were also high. These findings suggest that the fundamental defect in this patient is androgen resistance rather than defective androgen synthesis. Dihydrotestosterone formation from testosterone slices of epididymis and perineal skin was normal. The family history was uninformative. On endocrinologic, genetic, and phenotypic grounds the syndrome of incomplete testicular feminization can be separated from the complete form of testicular feminization and from familial incomplete male pseudohermaphroditism, Type 2. Additional studies will be required to determine whether this disorder is also distinct from the Type 1 form of familial incomplete male pseudohermaphromditism.


Elastography Study of Hamstring Behaviors during Passive Stretching.
The mechanical properties of hamstring muscles are usually inferred from global passive torque/angle relationships, in combination with adjoining tissues crossing the joint investigated. Shear modulus measurement provides an estimate of changes in muscle-tendon stiffness and passive tension. This study aimed to assess the passive individual behavior of each hamstring muscle in different stretching positions using shear wave elastography. The muscle shear modulus of each hamstring muscle was measured during a standardized slow passive knee extension (PKE, 80% of maximal range of motion) on eighteen healthy male volunteers. Firstly, we assessed the reliability of the measurements. Results were good for semitendinosus (ST, CV: 8.9%-13.4%), semimembranosus (SM, CV: 10.3%-11.2%) and biceps femoris long-head (BF-lh, CV: 8.6%-13.3%), but not for biceps femoris short-head (BF-sh, CV: 20.3%-44.9%). Secondly, we investigated each reliable muscle in three stretch positions: 70°, 90° and 110° of hip flexion. The results showed different values of shear modulus for the same amount of perceived stretch, with the highest measurements in the high-flexed hip situation. Moreover, individual muscles displayed different values, with values increasing or BF-lh, SM and ST, respectively. The inter-subject variability was 35.3% for ST, 27.4% for SM and 30.2% for BF-lh. This study showed that the hip needs to be high-flexed to efficiently tension the hamstrings, and reports a higher muscle-tendon stress tolerance at 110° of hip angle. In addition muscles have different passive behaviors, and future works will clarify if it can be linked with rate of injury.


Use of LEGO as a therapeutic medium for improving social competence.
A repeated-measures, waiting list control design was used to assess efficacy of a social skills intervention for autistic spectrum children focused on individual and group LEGO play. The intervention combined aspects of behavior therapy, peer modeling and naturalistic communication strategies. Close interaction and joint attention to task play an important role in both group and individual therapy activities. The goal of treatment was to improve social competence (SC) which was construed as reflecting three components: (1) motivation to initiate social contact with peers; (2) ability to sustain interaction with peers for a period of time: and (3) overcoming autistic symptoms of aloofness and rigidity. Measures for the first two variables were based on observation of subjects in unstructured situations with peers; and the third variable was assessed using a structured rating scale, the SI subscale of the GARS. Results revealed significant improvement on all three measures at both 12 and 24 weeks with no evidence of gains during the waiting list period. No gender differences were found on outcome, and age of clients was not correlated with outcome. LEGO play appears to be a particularly effective medium for social skills intervention, and other researchers and clinicians are encouraged to attempt replication of this work, as well as to explore use of LEGO in other methodologies, or with different clinical populations.


Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.
Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.


Biasing the perception of ambiguous vocal affect: a TMS study on frontal asymmetry.
Several sources of evidence point toward a link between asymmetry of prefrontal brain activity and approach-withdrawal tendencies. Here, we tested the causal nature of this link and examined if the categorization of an ambiguous approach- or withdrawal-related vocal signal can be biased by manipulating left and right frontal neural activity. We used voice morphing of affective non-verbal vocalizations to create individually tailored affectively ambiguous stimuli on an Anger-Fear continuum-two emotions that represent extremes on the approach-withdrawal dimension. We tested perception of these stimuli after 10 min of low-frequency repetitive transcranial magnetic stimulation over left or right dorsolateral prefrontal cortex or over the vertex (control), a technique that has transient inhibitory effects on the targeted brain region. As expected, ambiguous stimuli were more likely perceived as expressing Anger (approach) than Fear (withdrawal) after right prefrontal compared with left prefrontal or control stimulation. These results provide the first evidence that the manipulation of asymmetrical activity in prefrontal cortex can change the explicit categorization of ambiguous emotional signals.


Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients.
Twelve postmenopausal women suffering from advanced breast cancer had plasma estrogens, androgens, cortisol, and gonadotropins determined before therapy and during treatment with megestrol acetate (MA) in oral doses escalated from 40 to 160 mg. The plasma clearance and production rate of estrone and estrone sulfate were determined before treatment and after 4 weeks of therapy with 160 mg MA. Treatment with MA suppressed plasma levels of dehydroepiandrosterone sulfate, androstenedione, and cortisol in a dose-dependent manner to <10% of pretreatment values. Plasma testosterone, estradiol, estrone, and estrone sulfate were suppressed to 18-29% of pretreatment values, whereas the gonadotropins were suppressed to 35-52%. The plasma clearance rates of estrone and estrone sulfate were increased by a mean value of 23.7% (P < 0.01) and 23.5% (P < 0.025), whereas the production rates were reduced by 76.7% (P < 0.0005) and 76.1% (P < 0.0005), respectively. Our findings indicate that MA causes profound suppression of adrenal steroid production but in addition suppresses ovarian secretion of androgens in postmenopausal breast cancer patients. The reduction in plasma estrogens is comparable to values obtained with commonly used aromatase inhibitors and may be responsible for its antitumor effects in breast cancer.


Complicated skin and soft tissue infection.
Skin and soft tissue infections (SSTIs) are common, and complicated SSTIs (cSSTIs) are the more extreme end of this clinical spectrum, encompassing a range of clinical presentations such as deep-seated infection, a requirement for surgical intervention, the presence of systemic signs of sepsis, the presence of complicating co-morbidities, accompanying neutropenia, accompanying ischaemia, tissue necrosis, burns and bites. Staphylococcus aureus is the commonest cause of SSTI across all continents, although its epidemiology in terms of causative strains and antibiotic susceptibility can no longer be predicted with accuracy. The epidemiology of community-acquired and healthcare-acquired strains is constantly shifting and this presents challenges in the choice of empirical antibiotic therapy. Toxin production, particularly with Panton-Valentine leucocidin, may complicate the presentation still further. Polymicrobial infection with Gram-positive and Gram-negative organisms and anaerobes may occur in infections approximating the rectum or genital tract and in diabetic foot infections and burns. Successful management of cSSTI involves prompt recognition, timely surgical debridement or drainage, resuscitation if required and appropriate antibiotic therapy. The mainstays of treatment are the penicillins, cephalosporins, clindamycin and co-trimoxazole. β-Lactam/β-lactamase inhibitor combinations are indicated for polymicrobial infection. A range of new agents for the treatment of methicillin-resistant S. aureus infections have compared favourably with the glycopeptides and some have distinct pharmacokinetic advantages. These include linezolid, daptomycin and tigecycline. The latter and fluoroquinolones with enhanced anti-Gram-positive activity such as moxifloxacin are better suited for polymicrobial infection.


A genomic random interval model for statistical analysis of genomic lesion data.
Tumors exhibit numerous genomic lesions such as copy number variations, structural variations and sequence variations. It is difficult to determine whether a specific constellation of lesions observed across a cohort of multiple tumors provides statistically significant evidence that the lesions target a set of genes that may be located across different chromosomes but yet are all involved in a single specific biological process or function. We introduce the genomic random interval (GRIN) statistical model and analysis method that evaluates the statistical significance of the abundance of genomic lesions that overlap a specific locus or a pre-defined set of biologically related loci. The GRIN model retains certain biologically important properties of genomic lesions that are ignored by other methods. In a simulation study and two example analyses of leukemia genomic lesion data, GRIN more effectively identified important loci as significant than did three methods based on a permutation-of-markers model. GRIN also identified biologically relevant pathways with a significant abundance of lesions in both examples. An R package will be freely available at CRAN and www.stjuderesearch.org/site/depts/biostats/software.


Augmented cross-sectional studies with abbreviated follow-up for estimating HIV incidence.
Cross-sectional HIV incidence estimation based on a sensitive and less-sensitive test offers great advantages over the traditional cohort study. However, its use has been limited due to concerns about the false negative rate of the less-sensitive test, reflecting the phenomenon that some subjects may remain negative permanently on the less-sensitive test. Wang and Lagakos (2010, Biometrics 66, 864-874) propose an augmented cross-sectional design that provides one way to estimate the size of the infected population who remain negative permanently and subsequently incorporate this information in the cross-sectional incidence estimator. In an augmented cross-sectional study, subjects who test negative on the less-sensitive test in the cross-sectional survey are followed forward for transition into the nonrecent state, at which time they would test positive on the less-sensitive test. However, considerable uncertainty exists regarding the appropriate length of follow-up and the size of the infected population who remain nonreactive permanently to the less-sensitive test. In this article, we assess the impact of varying follow-up time on the resulting incidence estimators from an augmented cross-sectional study, evaluate the robustness of cross-sectional estimators to assumptions about the existence and the size of the subpopulation who will remain negative permanently, and propose a new estimator based on abbreviated follow-up time (AF). Compared to the original estimator from an augmented cross-sectional study, the AF estimator allows shorter follow-up time and does not require estimation of the mean window period, defined as the average time between detectability of HIV infection with the sensitive and less-sensitive tests. It is shown to perform well in a wide range of settings. We discuss when the AF estimator would be expected to perform well and offer design considerations for an augmented cross-sectional study with abbreviated follow-up.


Distinction between coordination and phosphine ligand oxidation: interactions of di- and triphosphines with Pn(3+) (Pn = P, As, Sb, Bi).
Reactions of polydentate phosphines with sources of Pn(3+) (Pn = P, As, Sb, Bi) yield complexes of Pn(1+) (Pn = P, As) or Pn(3+) (Pn = Sb, Bi) acceptors. The distinction between coordination of a phosphine center to Pn and oxidation of a phosphine ligand is dependent on Pn. The first structurally verified triphosphine complexes of Sb(III) and Bi(III) acceptors are reported.


Implicit and explicit prior information in near-infrared spectral imaging: accuracy, quantification and diagnostic value.
Near-infrared spectroscopy (NIRS) of tissue provides quantification of absorbers, scattering and luminescent agents in bulk tissue through the use of measurement data and assumptions. Prior knowledge can be critical about things such as (i) the tissue shape and/or structure, (ii) spectral constituents, (iii) limits on parameters, (iv) demographic or biomarker data, and (v) biophysical models of the temporal signal shapes. A general framework of NIRS imaging with prior information is presented, showing that prior information datasets could be incorporated at any step in the NIRS process, with the general workflow being: (i) data acquisition, (ii) pre-processing, (iii) forward model, (iv) inversion/reconstruction, (v) post-processing, and (vi) interpretation/diagnosis. Most of the development in NIRS has used ad hoc or empirical implementations of prior information such as pre-measured absorber or fluorophore spectra, or tissue shapes as estimated by additional imaging tools. A comprehensive analysis would examine what prior information maximizes the accuracy in recovery and value for medical diagnosis, when implemented at separate stages of the NIRS sequence. Individual applications of prior information can show increases in accuracy or improved ability to estimate biochemical features of tissue, while other approaches may not. Most beneficial inclusion of prior information has been in the inversion/reconstruction process, because it solves the mathematical intractability. However, it is not clear that this is always the most beneficial stage.


Goals-to-Discharge Patient Checklist: Implementing a Program to Optimize Recovery After Surgery for Patients With Colorectal Cancer.
Fast-track or enhanced recovery after surgery (ERAS) pathways are evidence-based perioperative guides that promote stress reduction and earlier return to function following surgery. They emphasize preoperative counseling, nutrition optimization, analgesia standardization, fluid and electrolyte balance, minimally invasive approaches, and early ambulation. Although ERAS pathways were implemented in 2016 on a 43-bed postoperative colorectal medical-surgical unit, inpatient stays remained beyond the projected two-day length of stay (LOS). A quality improvement team was formed and an eight-week pilot project was initiated in 2018. The project included the implementation of a laminated bedside goals-to-discharge checklist in the immediate postoperative period.


A biologic model for assessment of osseous strain patterns and plating systems in the human maxilla.
This study was conducted to examine a biomechanical model and to help answer fundamental questions that relate to rigid plate fixation in the maxilla. Specifically, we sought to elucidate the principal strain patterns generated in the maxilla secondary to masticatory forces as well as the amount of permanent deformational changes incurred due to these loading forces. Cadaveric heads with the mandible removed were defleshed and placed in a 2-part testing rig to hold and position the skull for testing in a standard material testing system. Rosette strain gages were attached at predefined points on the skull, and an Instron machine was used to load the skull through the loading port on the tray. A Le Fort I osteotomy was then performed on the skull, and a Walter Lorenz Ultra-Micro plating system was applied by a surgeon to reconnect the upper jaw. A 2-mm gap was left at the line of the osteotomy, and a transducer was attached to measure closure of the gap. Again the skull was loaded with the Instron (Canton, MA) machine. The results indicate a linear relationship exists with both maximum (tensile) and minimum (compressive) strain patterns relative to incremental load placement on the intact maxilla. The strain patterns after the Le Fort I osteotomy and plating were different and less linear. The differential variable reluctance transducer data showed a low rate of closure or transient increase in the gap at low loads (0 to 15 kilopond [kp] range) and a steeper slope of closure during high loads (15 to 60 kp range). It is also evident that axial loading forces cause permanent deformation and failure of osseous plating systems predominantly through bending. This model provides a foundation of knowledge regarding biomechanical strains in the maxilla subjected to static compressive loads in the force range of mastication. In addition, it serves as a comparative reference to assess rigidity of various craniofacial plating systems and to validate proposed standardized synthetic models. With the advent of increasingly precise surgery and new plating systems, this model can be used to help guide placement and design of plating systems; thereby allowing for ideal stabilization and optimizing surgical outcome.


Human Infection Challenge with Serotype 3 Pneumococcus.
Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 μl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated (n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.


Pediatric clinicians can help reduce rates of early childhood caries: effects of a practice based intervention.
Early childhood caries (ECC) is a serious and preventable disease which pediatric clinicians can help address by counseling to reduce risk. We implemented a multifaceted practice-based intervention in a pediatric outpatient clinic treating children vulnerable to ECC (N = 635), comparing results to those from a similar nearby clinic providing usual care (N = 452). We provided communication skills training using the approach of patient centered counseling, edited the electronic medical record to prompt counseling, and provided parents/caregivers with an educational brochure. We assessed changes in provider knowledge about ECC after the intervention, and examined providers' counseling practices and incidence of ECC over time by site, controlling for baseline ECC, patient sociodemographics and parents'/caregivers' practice of risk factors (diet, oral hygiene, tooth-monitoring), among 1045 children with complete data. Provider knowledge about ECC increased after the intervention training (percentage correct answers improved from 66% to 79%). Providers at the intervention site used more counseling strategies, which persisted after adjustment for sociodemographic characteristics. Children at the intervention site had a 77% reduction in risk for developing ECC at follow up, after controlling for age and race/ethnicity, sociodemographics and ECC risk factors; P <or= 0.004. The multifaceted intervention was associated with increased provider knowledge and counseling, and significantly attenuated incidence of ECC. If validated by additional studies, similar interventions could have the potential to make a significant public health impact on reducing ECC among young children.


Controlling shape and position of vascular formation in engineered tissues by arbitrary assembly of endothelial cells.
Cellular self-assembly based on cell-to-cell communication is a well-known tissue organizing process in living bodies. Hence, integrating cellular self-assembly processes into tissue engineering is a promising approach to fabricate well-organized functional tissues. In this research, we investigated the capability of endothelial cells (ECs) to control shape and position of vascular formation using arbitral-assembling techniques in three-dimensional engineered tissues. To quantify the degree of migration of ECs in endothelial network formation, image correlation analysis was conducted. Positive correlation between the original positions of arbitrarily assembled ECs and the positions of formed endothelial networks indicated the potential for controlling shape and position of vascular formations in engineered tissues. To demonstrate the feasibility of controlling vascular formations, engineered tissues with vascular networks in triangle and circle patterns were made. The technique reported here employs cellular self-assembly for tissue engineering and is expected to provide fundamental beneficial methods to supply various functional tissues for drug screening and regenerative medicine.


Contact tracing during the COVID-19 outbreak: a protocol for enabling rapid learning from experiences and exploring the psychological impact on contact tracers.
Background: Given the unprecedented nature of the COVID-19 pandemic, the Irish health system required the redeployment of public sector staff and the recruitment of dedicated contact tracing staff in the effort to contain the spread of the virus. Contact tracing is crucial for effective disease control and is normally carried out by public health teams. Contact tracing staff are provided with rapid intensive training but are operating in a dynamic environment where processes and advice are adapting continuously. Real-time data is essential to inform strategy, coordinate interconnected processes, and respond to needs . Given that many contact tracers have been newly recruited or redeployed, they may not have significant experience in healthcare and may experience difficulties in managing the anxieties and emotional distress of the public. Aim: (i) identify emerging needs and issues and feed this information back to the Health Service Executive for updates to the COVID-19 Contact Management Programme (CMP); (ii) understand the psychological impact on contact tracers and inform the development of appropriate supports. Methods: We will use a mixed-methods approach. A brief online survey will be administered at up to three time points during 2021 to measure emotional exhaustion, anxiety, general health, and stress of contact tracing staff, identify tracing systems or processes issues, as well as issues of concern and confusion among the public. Interviews will also be conducted with a subset of participants to achieve a more in-depth understanding of these experiences. Observations may be conducted in contact tracing centres to document processes, practices, and explore any local contextual issues. Impact: Regular briefs arising from this research with data, analysis, and recommendations will aim to support the work of the CMP to identify problems and implement solutions. We will deliver regular feedback on systems issues; challenges; and the psychological well-being of contact tracing staff.


Water-sanitation-hygiene mapping: an improved approach for data collection at local level.
Strategic planning and appropriate development and management of water and sanitation services are strongly supported by accurate and accessible data. If adequately exploited, these data might assist water managers with performance monitoring, benchmarking comparisons, policy progress evaluation, resources allocation, and decision making. A variety of tools and techniques are in place to collect such information. However, some methodological weaknesses arise when developing an instrument for routine data collection, particularly at local level: i) comparability problems due to heterogeneity of indicators, ii) poor reliability of collected data, iii) inadequate combination of different information sources, and iv) statistical validity of produced estimates when disaggregated into small geographic subareas. This study proposes an improved approach for water, sanitation and hygiene (WASH) data collection at decentralised level in low income settings, as an attempt to overcome previous shortcomings. The ultimate aim is to provide local policymakers with strong evidences to inform their planning decisions. The survey design takes the Water Point Mapping (WPM) as a starting point to record all available water sources at a particular location. This information is then linked to data produced by a household survey. Different survey instruments are implemented to collect reliable data by employing a variety of techniques, such as structured questionnaires, direct observation and water quality testing. The collected data is finally validated through simple statistical analysis, which in turn produces valuable outputs that might feed into the decision-making process. In order to demonstrate the applicability of the method, outcomes produced from three different case studies (Homa Bay District-Kenya-; Kibondo District-Tanzania-; and Municipality of Manhiça-Mozambique-) are presented.


Evaluation of Color and Width of Attached Gingiva Gain in Two Surgical Techniques: Free Gingival Graft and Connective Tissue Graft Covered By Thin Mucosal Flap, a Clinical Trial.
The periodontal health and marginal stability of gingiva can be negatively affected by a number of dental conditions in association with deficiency of attached gingiva. This study aimed to compare the color and width of tissue grafted by two surgical techniques of keratinized gingival augmentation, namely free gingival graft(FGG) and connective tissue graft (CTG) covered by thin mucosal flap . This clinical trial was performed on 15 adult individuals. The patients showed less than 2mm keratinized gingiva on two different recipient sides. One side was to be treated with CTG as the test group and the other side to be treated with FGG as the control group. The amount of keratinized gingiva before the surgery, size of grafted tissue during the surgery and 6 month after the surgery was documented. Six months after healing, the test and control sides were compared in terms of the width of generated gingiva on both sides, and the color match of the grafted areas with the surrounding gingiva or mucosa. The color of the grafted areas was determined and compared by using both professional evaluation and digital evaluation. In digital evaluation, ∆E (which shows color mismatch) was higher in FGG. In professional evaluation, visual analogue scale (VAS) was used by two blinded periodontists. The mean VAS in FGG was less than CTG. The mean increase of gingival width was higher in CTG. The increased width in CTG technique was more than that in FGG technique. This difference was statistically, but not clinically, significant. Higher ∆E in control side and higher mean VAS CTG both showed better color adaptation of CTG side. FGG can be used in case of increasing keratinized gingiva, vestibular depth, and in patients with low smile line without esthetic concerns. However, using connective tissue in the underlying thin mucosal layer is preferred for gingival augmentation if there are adequate vestibule depth and esthetic concerns, like in maxillary canine.