Effect of mammographic service screening on stage at presentation of breast cancers in Sweden.
Previous results have shown a reduction in mortality with service screening in Sweden on the order of 40%. If the rate of tumors at a later stage were similarly reduced, this would give further support to the mortality findings. The rates of lymph node-positive cancers, of tumors >2 cm in pathological size, and of tumors of TNM stage II or worse before and after the introduction of screening were compared in 13 areas in Sweden, adjusted for changes in overall incidence during the period of study and stratified by age (40-49 and 50-69 years). Data were obtained on a total of 23,092 cancers and 10,177,113 person-years of observation. In women exposed to screening in the screening epoch, there was a significant 45% reduction in tumors of size >2 cm compared with the prescreening (relative risk [RR]=0.55, 95% confidence interval [CI]: 0.46-0.66) in the 40-49 age group, and a 33% reduction in the 50-69 group (RR=0.67, 95% CI: 0.62-0.72). For lymph node-positive and stage II+ disease, there were smaller but still significant reductions. No reduction in incidence in later-stage disease was observed in the unexposed women in the screening epoch. Screening has significantly and substantially reduced the rates of larger tumors and lymph node-positive breast cancer in Sweden, and the magnitude of the reduction is consistent with the reduction in breast cancer mortality.


Whole-Body Diffusion-Weighted Imaging in Chronic Recurrent Multifocal Osteomyelitis in Children.
Chronic recurrent multifocal osteomyelitis/ chronic non-bacterial osteomyelitis (CRMO/ CNO) is a rare auto-inflammatory disease and typically manifests in terms of musculoskeletal pain. Because of a high frequency of musculoskeletal disorders in children/ adolescents, it can be quite challenging to distinguish CRMO/ CNO from nonspecific musculoskeletal pain or from malignancies. The purpose of this study was to evaluate the visibility of CRMO lesions in a whole-body diffusion-weighted imaging (WB-DWI) technique and its potential clinical value to better characterize MR-visible lesions. Whole-body imaging at 3T was performed in 16 patients (average: 13 years) with confirmed CRMO. The protocol included 2D Short Tau Inversion Recovery (STIR) imaging in coronal and axial orientation as well as diffusion-weighted imaging in axial orientation. Visibility of lesions in DWI and STIR was evaluated by two readers in consensus. The apparent diffusion coefficient (ADC) was measured for every lesion and corresponding reference locations. A total of 33 lesions (on average 2 per patient) visible in STIR and DWI images (b = 800 s/mm2 and ADC maps) were included, predominantly located in the long bones. With a mean value of 1283 mm2/s in lesions, the ADC was significantly higher than in corresponding reference regions (782 mm2/s). By calculating the ratio (lesion to reference), 82% of all lesions showed a relative signal increase of 10% or higher and 76% (25 lesions) showed a signal increase of more than 15%. The median relative signal increase was 69%. This study shows that WB-DWI can be reliably performed in children at 3T and predominantly, the ADC values were substantially elevated in CRMO lesions. WB-DWI in conjunction with clinical data is seen as a promising technique to distinguish benign inflammatory processes (in terms of increased ADC values) from particular malignancies.


Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome.
Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet-Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.


Prevalence and correlates of alcohol misuse among returning Afghanistan and Iraq veterans.
Several studies have reported high rates of alcohol misuse and low rates of substance use treatment among OEF/OIF military service members. This study assessed the prevalence and correlates of alcohol misuse and the factors associated with treatment utilization among recently returned National Guard service members. The sample included 585 members of the National Guard who volunteered to complete an anonymous survey assessing mental health and substance use problems, functional status, and past treatment experiences. Bivariate and multivariate logistic regression analyses were performed examining the significance of associations between alcohol misuse and mental health service use as outcomes and demographic variables, mental health symptoms, and military service characteristics as predictors. Barriers to treatment and factors facilitating treatment were also examined. Thirty-six percent of the service members met criteria for alcohol misuse. Of those misusing alcohol, 31% reported receiving any mental health treatment and 2.5% reported receiving specific substance use treatment in the past year. The barrier to treatment most commonly endorsed by those misusing alcohol was concern that the information about treatment would appear in their records. Among those misusing alcohol who had received services, spouses were most commonly endorsed as facilitating the pursuit of care. Rates of alcohol misuse are high and rates of substance use treatment are low among National Guard service members. Additional research is needed to identify means of overcoming barriers to care and establish more effective approaches to facilitate linkage to care and receipt of appropriate interventions.


Outcomes of Aortic Surgery for Abdominal Aortic Graft Infections.
Literature on postoperative outcomes following aortic surgery for aortic graft infection (AGI) is limited by relatively small sample sizes, resulting in lack of national benchmarks for quality of care. We report in-hospital outcomes following abdominal aortic surgery for AGI and identify factors associated with postoperative complications using the Nationwide Inpatient Sample (NIS) database. Patients who underwent aortic graft resection for AGI were identified from the 2002 to 2008 NIS database, a multicenter database capturing 20% of all US admissions. Multivariable logistic regression analyses were performed. Among 394 patients (men: 73.4%) who underwent abdominal aortic surgery for AGI, 53% of the admissions were emergent/urgent. A significant trend for decreasing number of abdominal aortic surgery for AGIs per year was observed (Pearson r correlation: -.96; P = .0006). Over the same time span, a significant correlation was also seen with decrease in open and increase in endovascular aortic aneurysm repairs in the NIS database. In-hospital rates of overall postoperative morbidity and mortality were 68.3% and 19.8%, respectively. In-hospital rates of postoperative respiratory failure, renal failure, and cardiac arrest were 35.5%, 14.2%, and 8.9%, respectively. Median length of stay was 26 days, with median hospital charges being US$184 162. On multivariable analysis, increase in age per year (odds ratio [OR] 1.07; 95% confidence interval [CI]: 1.03-1.12) was independently associated with postoperative morbidity, while higher hospital volume for this procedure was protective (OR: 0.71; 95% CI: 0.56-0.89). No preoperative factors were independently associated with postoperative mortality. Incidence of abdominal aortic surgery for AGI has progressively declined over the span of our study in association with decreased open and increased endovascular aortic aneurysm repairs. Aortic surgery for AGI is associated with very high morbidity and mortality rates along with prolonged lengths of stay and elevated hospital charges. The outcomes of operations for AGI are better in younger patients and higher volume hospitals.


Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses from the rostral ventrolateral medulla.
Increased dietary salt exaggerates arterial blood pressure (ABP) responses evoked from the rostral ventrolateral medulla (RVLM). The present study determined whether these enhanced pressor responses were directly attributable to a greater increase in sympathetic nerve activity (SNA) and whether these enhanced responses were balanced by a greater responsiveness of RVLM neurons to inhibitory input. Male Sprague-Dawley rats were fed normal chow and given access to either water or a 1% NaCl solution for 14 days. Injection of l-glutamate (0.03, 0.1, 1.0, and 3.0 nmol) into the RVLM produced a significantly greater increase in renal SNA, splanchnic SNA, and ABP in rats drinking 1% NaCl versus water. Conversely, injection of the inhibitory amino acid gamma-aminobutyric acid (0.1, 1.0, and 10 nmol) into the RVLM produced significantly greater decreases in renal SNA, splanchnic SNA, and ABP of rats drinking 1% NaCl versus water. These enhanced SNA and ABP responses to l-glutamate and gamma-aminobutyric acid were not observed in rats drinking 1% NaCl for 1 or 7 days but were present in rats drinking 1% NaCl for 21 days. Moreover, the dietary salt-induced enhancement of both sympathoexcitatory and sympathoinhibitory responses from the RVLM persisted after the 1% NaCl solution was replaced with water for 1, but not 7, days. These findings indicate that the potentiated ABP responses observed previously are mediated by parallel changes in SNA, and these responses depend on a slowly developing and reversible form of neuronal plasticity.


Photosystem trap energies and spectrally-dependent energy-storage efficiencies in the Chl d-utilizing cyanobacterium, Acaryochloris marina.
Acaryochloris marina is the only species known to utilize chlorophyll (Chl) d as a principal photopigment. The peak absorption wavelength of Chl d is redshifted ≈40nm in vivo relative to Chl a, enabling this cyanobacterium to perform oxygenic phototrophy in niche environments enhanced in far-red light. We present measurements of the in vivo energy-storage (E-S) efficiency of photosynthesis in A. marina, obtained using pulsed photoacoustics (PA) over a 90-nm range of excitation wavelengths in the red and far-red. Together with modeling results, these measurements provide the first direct observation of the trap energies of PSI and PSII, and also the photosystem-specific contributions to the total E-S efficiency. We find the maximum observed efficiency in A. marina (40±1% at 735nm) is higher than in the Chl a cyanobacterium Synechococcus leopoliensis (35±1% at 690nm). The efficiency at peak absorption wavelength is also higher in A. marina (36±1% at 710nm vs. 31±1% at 670nm). In both species, the trap efficiencies are ≈40% (PSI) and ≈30% (PSII). The PSI trap in A. marina is found to lie at 740±5nm, in agreement with the value inferred from spectroscopic methods. The best fit of the model to the PA data identifies the PSII trap at 723±3nm, supporting the view that the primary electron-donor is Chl d, probably at the accessory (Chl(D1)) site. A decrease in efficiency beyond the trap wavelength, consistent with uphill energy transfer, is clearly observed and fit by the model. These results demonstrate that the E-S efficiency in A. marina is not thermodynamically limited, suggesting that oxygenic photosynthesis is viable in even redder light environments.


Whole-foods, plant-based diet alleviates the symptoms of osteoarthritis.
Objective. To evaluate the effectiveness of a whole-foods, plant-based diet (WFPB) to reduce symptoms of osteoarthritis. Methods. Six-week, prospective randomized open-label study of patients aged 19-70 with osteoarthritis. Participants were randomized to a WFPB (intervention) or continuing current diet (control). Outcomes were assessed by mixed models analysis of participant self-assessed weekly SF-36v2 domain t scores, weekly Patient Global Impression of Change (PGIC) scales, and mean weekly Visual Analog Scale (VAS) pain assessment. Mixed models analysis also evaluated pre-post change from baseline level for standard clinical measures: weight, BMI, body temperature, pulse, and blood pressure. Results. Forty participants were randomized. Thirty-seven of them, 18 control and 19 intervention, completed the study. The intervention group reported a significantly greater improvement than the control group in SF-36v2 energy/vitality, physical functioning, role physical, and the physical component summary scale. The differences between the intervention and control PGIC scales were statistically significant over time. Intervention group improvement in VAS weekly mean was also significantly greater than that of the control group from week 2 onward. Conclusion. Study results suggest that a whole-foods, plant-based diet significantly improves self-assessed measures of functional status among osteoarthritis patients.


Central cardiovascular effects of physostigmine in humans.
Central cholinergic control of pulse rate and blood pressure has seldom been studied in humans. In the current study we contrasted the cardiovascular effects of the centrally acting cholinesterase inhibitor physostigmine, which increases central and peripheral acetylcholine levels, with those of saline placebo and with those of the non-centrally acting cholinesterase inhibitor neostigmine, which only increases peripheral acetylcholine levels. We found that physostigmine, in contrast to neostigmine and saline, caused significant and often profound increases in pulse rate and blood pressure levels in humans. Thus, we conclude that acetylcholine may have a role in central cardiovascular regulation in humans. We also found that administration of physostigmine may cause net increases in pulse of up to 74 beats/minute, systolic blood pressure increases of up to 50 mm Hg, and diastolic increases of up to 45 mm Hg. Such increases could be dangerous in elderly patients with concomitant cerebrovascular or coronary circulation disorders.


Maternal parity and diet (n-3) polyunsaturated fatty acid concentration influence accretion of brain phospholipid docosahexaenoic acid in developing rats.
The long-chain PUFA, docosahexaenoic acid [22:6(n-3), DHA], a major component of neuronal membrane phospholipids, accumulates in brain during late prenatal and early neonatal development and is essential for optimal attentional and cognitive function. Because all nutrition is supplied to the developing fetus/neonate by the mother and maternal DHA status is affected by parity, this study examined the effects of maternal diet and parity on DHA accretion in the developing brain. Whole brain total phospholipid fatty acid composition was determined by TLC and GC in weanling male Long-Evans rats (n = 5) from the 1st, 2nd, 3rd, or 4th litters of dams fed diets containing alpha-linolenic acid (ALA), containing ALA and preformed DHA (ALA + DHA), or lacking ALA (low-ALA). First-litter low-ALA offspring exhibited a decrease in phospholipid fatty acid DHA content to 68% of 1st-litter ALA pups. DHA in 2nd-litter low-ALA pups was further decreased to 55% of 1st-litter ALA pups, but further decreases were not observed in subsequent litters. DHA levels increased 15-20% in 2nd to 4th-litter ALA + DHA pups and 11% in 4th-litter ALA pups compared with 1st-litter ALA pups. These findings demonstrate that maternal diet and parity interact to affect offspring brain DHA status and suggest that maternal multiparity may place offspring at greater risk of decreased accretion of brain DHA if the maternal diet contains insufficient (n-3) PUFA.


Associations between BMI and home, school and route environmental exposures estimated using GPS and GIS: do we see evidence of selective daily mobility bias in children?
This study examined whether objective measures of food, physical activity and built environment exposures, in home and non-home settings, contribute to children's body weight. Further, comparing GPS and GIS measures of environmental exposures along routes to and from school, we tested for evidence of selective daily mobility bias when using GPS data. This study is a cross-sectional analysis, using objective assessments of body weight in relation to multiple environmental exposures. Data presented are from a sample of 94 school-aged children, aged 5-11 years. Children's heights and weights were measured by trained researchers, and used to calculate BMI z-scores. Participants wore a GPS device for one full week. Environmental exposures were estimated within home and school neighbourhoods, and along GIS (modelled) and GPS (actual) routes from home to school. We directly compared associations between BMI and GIS-modelled versus GPS-derived environmental exposures. The study was conducted in Mebane and Mount Airy, North Carolina, USA, in 2011. In adjusted regression models, greater school walkability was associated with significantly lower mean BMI. Greater home walkability was associated with increased BMI, as was greater school access to green space. Adjusted associations between BMI and route exposure characteristics were null. The use of GPS-actual route exposures did not appear to confound associations between environmental exposures and BMI in this sample. This study found few associations between environmental exposures in home, school and commuting domains and body weight in children. However, walkability of the school neighbourhood may be important. Of the other significant associations observed, some were in unexpected directions. Importantly, we found no evidence of selective daily mobility bias in this sample, although our study design is in need of replication in a free-living adult sample.


Immediate Impact of Acute Elevation of Intraocular Pressure on Cortical Visual Motion Processing.
To physiologically examine the impairment of cortical sensitivity to visual motion during acute elevation of intraocular pressure (IOP). Motion processing in the cat brain is well characterized, its X and Y cell visual pathways being functionally analogous to parvocellular and magnocellular pathways in primates. Using this model, we performed ocular anterior chamber perfusion to reversibly elevate IOP over a range from 30 to 90 mm Hg while monitoring cortical activity with intrinsic signal optical imaging. Drifting random-dot fields and gratings were used to characterize cortical population responses to motion direction and orientation in early visual areas 17 and 18. We found that acute IOP elevations at 50 mm Hg and above, which is often observed in acute glaucoma, suppressed cortical motion direction responses. This suppression was more profound in area 17 than in area 18, and more profound in central than peripheral visual field (eccentricities 0°-4° vs. 4°-8°) within area 17. In addition, orientation responses were more suppressed than motion direction responses for the same IOP modulation. In contrast to human chronic glaucoma that may cause greater dysfunction in large-cell magnocellular than in small-cell parvocellular visual pathways, our direct measurement of cortical processing networks implies that the small X-cell pathway shows greater vulnerability to acute IOP elevation than the large Y-cell pathway in visual motion processing. The results demonstrate that fine discrimination mechanisms for motion in the central visual field are particularly impacted by acute IOP attacks, suggesting a neural basis for immediate visual deficits in the fine motion perception of acute glaucoma patients.


Adjuvant carboplatin therapy in patients with clinical stage 1 testicular seminoma: is long-term morbidity increased?
Clinical stage (CS) 1 testicular seminoma is cured in almost 100% of cases following either retroperitoneal radiotherapy, carboplatin monotherapy, or surveillance strategies. Little is known about potential long-term effects of carboplatin. We, therefore, examined late sequelae of this drug in seminoma patients. We retrospectively identified 451 patients with CS1 testicular seminoma treated between 1994 and 2014, of whom 243 underwent carboplatin therapy [median follow-up (F/U) 96 months], 81 received radiotherapy (median F/U 142 months), and 127 underwent surveillance (median F/U 40 months). Satisfaction regarding management, as well as the following events during F/U, were analysed by questionnaire: subsequent malignant neoplasms (SMNs), cardiovascular events, arterial hypertension, peptic ulcer, tinnitus, peripheral neuropathy, hypogonadism, and infertility. The relative frequencies of the events were analysed using descriptive statistics. The frequency of observed SMNs was compared with the expected number. Patients receiving carboplatin tolerated the treatment less well (71.2%) than those under surveillance (81.9%). After carboplatin, 12 SMNs (5.0%) were noted vis-a-vis 5.0 expected. There were three cases of prostatic cancer and 3 melanomas among the SMNs. Half of these SMNs occurred early after treatment. Among the other health events, only reported hypogonadism (13.2%) appeared to be marginally increased in frequency. This study found a 2.4-fold higher than expected rate of SMN-and a slightly increased rate of hypogonadism-in the long-term period following carboplatin treatment. Although further studies are needed to confirm these preliminary findings, these results are probably informative for clinicians caring for seminoma patients.


Mitral valve repair for ischemic mitral regurgitation.
Mitral valve repair for ischemic mitral valve regurgitation remains controversial. In moderate mitral regurgitation (MR), controversy exists whether revascularization alone will be adequate to restore native valve geometry or whether intervention on the valve (repair) should be performed concomitantly. When MR is severe, the need for valve intervention is not disputed. Rather, the controversy is whether repair versus replacement should be undertaken. In contrast to degenerative or myxomatous disease that directly affects leaflet integrity and morphology, ischemic FMR results from a distortion and dilation of native ventricular geometry that normally supports normal leaflet coaptation. To address this, the first and most crucial step in successful valve repair is placement of an undersized, complete remodeling annuloplasty ring to restore the annulus to its native geometry. The following article outlines the steps for repair of ischemic mitral regurgitation.


Reference values of aortic pulse wave velocity in a large healthy population aged between 3 and 18 years.
The measurement of aortic pulse wave velocity (PWV(ao)) is an accepted marker in stratifying individual cardiovascular risk in adults. There is an increasing volume of evidence concerning impaired vascular function in different diseases in paediatric populations, but, unfortunately, only a few studies are available on the measurement of normal PWV(ao) values in children. The aim of our study was to determine the reference values of PWV(ao) in a large healthy population using a newly developed technique. Three thousand, three hundred and seventy-four healthy individuals (1802 boys) aged 3-18 years were examined by an invasively validated, occlusive, oscillometric device. The mean PWV(ao) values increased from 5.5 ± 0.3 to 6.5 ± 0.3 m/s (P < 0.05) in boys and from 5.6 ± 0.3 to 6.4 ± 0.3 m/s (P < 0.05) in girls. The increase, however, was not constant, and the values exhibited a flat period between the ages of 3 and 8 years in both sexes. The first pronounced increase occurred at the age of 12.1 years in boys and 10.4 years in girls. Moreover, between the ages of 3 and 8 years, the brachial SBP and mean blood pressures increased continuously and gradually, whereas the PWV(ao) remained unchanged. By contrast, beyond the age of 9 years, blood pressure and aortic stiffness trends basically moved together. Our study provides the largest database to date concerning arterial stiffness in healthy children and adolescents between the ages of 3 and 18 years, and the technology adopted proved easy to use in large paediatric populations, even at a very young age.


Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis.
Although lifelong combination antiretroviral therapy (ART) is recommended for all individuals with HIV, few data exist for pregnancy outcomes associated with ART initiation before conception. We assessed adverse pregnancy outcomes associated with ART initiated before conception compared with that of ART started after conception. We did a systematic review of studies from low-income, middle-income, and high-income countries by searching the Cochrane Central Register of Controlled Trials, Embase, LILACS, MEDLINE, Toxline, Web of Knowledge, and WHO Global Index Medicus and trials in progress (International Clinical Trials Registry Platform) for randomised trials, quasi-randomised trials, and prospective cohort studies done between Jan 1, 1980, and June 1, 2016, in which timing of ART initiation in pregnant women living with HIV was reported. We used the risk ratio (RR) and corresponding 95% CIs as the primary measure to assess the association between the selected outcomes and ART initiation before conception versus after conception. We used a random-effects model to pool risk ratios. We included 11 studies with 19 189 mother-infant pairs. Women who started ART before conception were significantly more likely to deliver preterm (pooled RR 1·20, 95% CI 1·01-1·44) or very preterm (1·53, 1·22-1·92), or to have low-birthweight infants (1·30, 1·04-1·62) than were those who began ART after conception. Few data exist for neonatal mortality. The risk of very low birthweight, small for gestational age, severe small for gestational age, stillbirth, and congenital anomalies did not differ significantly between women who were taking ART before conception and those who began ART after conception. The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but data for the extent and severity of these risks are scarce and of low quality. As use of ART before conception rapidly increases globally, monitoring for potential adverse pregnancy outcomes will be crucial. WHO.


Modulation of cortical excitability can speed up blindsight but not improve it.
Blindsight has been widely investigated and its properties documented. One property still debated and contested is the puzzling absence of phenomenal visual percepts of visual stimuli that can be detected with perfect accuracy. We investigated the possibility that phenomenal visual percepts of exogenous visual stimuli in patient GY might be induced by using transcranial direct current stimulation. High contrast and low contrast stimuli were presented as a moving grating in his blind hemifield. When left area MT/V5 was anodally stimulated during the presentation of high-contrast gratings, he never reported a phenomenal percept of a moving grating but showed perfect blindsight performance. When applied along with low contrast gratings, for which accuracy was titrated to 60-70 %, performance did not improve but responses were significantly faster. Cathodal stimulation had no effect. Results are explained in the framework of GY's reorganized cortical connexions and oscillatory patterns known to be involved in awareness in GY. The apparent presence of phenomenal visual percepts in earlier studies is shown to be a semantic confusion about what he means when he says that he sees in his blind field.


Hormone replacement therapy after surgery for epithelial ovarian cancer.
Women who have undergone surgical treatment for epithelial ovarian cancer (EOC) may develop menopausal symptoms due to immediate loss of ovarian function following surgery and chemotherapy. Women may experience vasomotor symptoms, sleep disturbance, difficulty concentrating, sexual dysfunction, vaginal symptoms and accelerated osteoporosis. Although hormone replacement therapy (HRT) is the most effective treatment to relieve these symptoms, its safety has been questioned for women with EOC. To assess the safety and efficacy of HRT for menopausal symptoms in women surgically treated for EOC. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 6), MEDLINE via Ovid (1946 to 12 June 2019) and Embase via Ovid (1980 to 2019, week 23). We also handsearched conference reports and trial registries. There was no language restriction. We included randomized controlled trials (RCTs) with participants of any age and menopausal status who had undergone surgery for EOC and, after diagnosis and treatment, used any regimen and duration of HRT compared with placebo or no hormone therapy. We also included trials comparing different regimens or duration of administration of HRT. Two review authors independently identified studies that met the inclusion criteria. They used Covidence to extract study characteristics, outcome data and to assess methodological quality of the included studies. Our search strategy identified 2617 titles, of which 2614 titles were excluded. Three studies, involving 350 women, met our inclusion criteria. Two of the studies included pre and postmenopausal women, and the third only included premenopausal women. The overall age range of those women included in the studies was 20 to 89.6 years old, with a median follow-up ranging from 31.4 months to 19.1 years. The geographical distribution of participants included Europe, South Africa and China. All stages and histological subtypes were included in two of the studies, but stage IV disease had been excluded in the third. The three included studies used a variety of HRT regimens (conjugated oestrogen with or without medroxyprogesterone and with or without nylestriol) and HRT administrations (oral, patch and implant), In all studies, the comparisons were made versus women who had not received HRT. The studies were at low or unclear risk of selection and reporting bias, and at high risk of performance, detection and attrition bias. The certainty of the evidence was low for overall survival and progression-free survival, and very low for quality-of-life assessment, incidence of breast cancer, transient ischaemic attack (TIA), cerebrovascular accident (CVA) and myocardial infarction (MI). Meta-analysis of these studies showed that HRT may improve overall survival (hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.54 to 0.93; 350 participants, 3 studies; low-certainty evidence). Quality-of-life assessment by use of the EORTC-C30 questionnaire was performed only in one study. We are uncertain whether HRT improves or reduces quality of life as the certainty of the evidence was assessed as very low (mean difference (MD) 13.67 points higher, 95% CI 9.26 higher to 18.08 higher; 1 study; 75 participants; very low-certainty evidence). Likewise, HRT may make little or no difference to progression-free survival (HR 0.76, 95% CI 0.57 to 1.01; 275 participants, 2 studies; low-certainty evidence). We are uncertain whether HRT improves or reduces the incidence of breast cancer (risk ratio (RR) 2.00, 95% CI 0.19 to 21.59; 225 participants, 2 studies; very low-certainty evidence); TIA (RR 5.00, 95% CI 0.24 to 102.42; 150 participants, 1 study; very low-certainty evidence); CVA (RR 0.67, 95% CI 0.11 to 3.88; 150 participants, 1 study; very low-certainty evidence); and MI (RR 0.20, 95% CI 0.01 to 4.10; 150 participants, 1 study; very low-certainty evidence). The incidence of gallstones was not reported in the included studies. Hormone replacement therapy may slightly improve overall survival in women who have undergone surgical treatment for EOC, but the certainty of the evidence is low. HRT may make little or no difference to quality of life, incidence of breast cancer, TIA, CVA and MI as the certainty of the evidence has been assessed as very low. There may be little or no effect of HRT use on progression-free survival. The evidence in this review is limited by imprecision and incompleteness of reported relevant outcomes and therefore the results should be interpreted with caution. Future well-designed RCTs are required as this is an important area to women experiencing menopausal symptoms following surgical treatment for ovarian cancer, especially as doctors are often reluctant to prescribe HRT in this scenario. The evidence in this review is too limited to support or refute that HRT is very harmful in this population.


Arterial pulsatility under phasic left ventricular assist device support.
The aim of this study is to understand whether the phasic Continuous Flow Left Ventricular Assist Device (CF-LVAD) support would increase the arterial pulsatility. A Micromed DeBakey CF-LVAD was used to apply phasic support in an ex-vivo experimental platform. CF-LVAD was operated over a cardiac cycle by phase-shifting the pulsatile pump control with respect to the heart cycle, in 0.05 s increments in each experiment. The pump flow rate was selected as the control variable and a reference model was used to operate the CF-LVAD at a pulsatile speed. Arterial pulse pressure was the highest (9 mmHg) when the peak pump flow is applied at the peak systole under varying speed CF-LVAD support over a cardiac cycle while it was the lowest (2 mmHg) when the peak pump flow was applied in the diastolic phase. The mean arterial pressure and mean CF-LVAD output were the same in each experiment while arterial pulse pressure and pulsatility index varied depending on the phase of reference pump flow rate signal. CF-LVAD speed should be synchronized considering the timing of peak systole over a cardiac cycle to increase the arterial pulsatility. Moreover, it is possible to decrease the arterial pulsatility under counter-pulsating CF-LVAD support.


Osmotic stimulation of vasopressin acutely impairs glucose regulation: a counterbalanced, crossover trial.
Epidemiological studies in humans show increased concentrations of copeptin, a surrogate marker of arginine vasopressin (AVP), to be associated with increased risk for type 2 diabetes. To examine the acute and independent effect of osmotically stimulated AVP, measured via the surrogate marker copeptin, on glucose regulation in healthy adults. Sixty subjects (30 females) participated in this crossover design study. On 2 trial days, separated by ≥7 d (males) or 1 menstrual cycle (females), subjects were infused for 120 min with either 0.9% NaCl [isotonic (ISO)] or 3.0% NaCl [hypertonic (HYPER)]. Postinfusion, a 240-min oral-glucose-tolerance test (OGTT; 75 g) was administered. During HYPER, plasma osmolality and copeptin increased (P < 0.05) and remained elevated during the entire 6-h protocol, whereas renin-angiotensin-aldosterone system hormones were within the lower normal physiological range at the beginning of the protocol and declined following infusion. Fasting plasma glucose did not differ between trials (P > 0.05) at baseline and during the 120 min of infusion. During the OGTT the incremental AUC for glucose from postinfusion baseline (positive integer) was greater during HYPER (401.5 ± 190.5 mmol/L·min) compared with the ISO trial (354.0 ± 205.8 mmol/L·min; P < 0.05). The positive integer of the AUC for insulin during OGTT did not differ between trials (HYPER 55,850 ± 36,488 pmol/L·min compared with ISO 57,205 ± 31,119 pmol/L·min). Baseline values of serum glucagon were not different between the 2 trials; however, the AUC of glucagon during the OGTT was also significantly greater in HYPER (19,303 ± 3939 ng/L·min) compared with the ISO trial (18,600 ± 3755 ng/L·min; P < 0.05). The present data indicate that acute osmotic stimulation of copeptin induced greater hyperglycemic responses during the oral glucose challenge, possibly due to greater glucagon concentrations.This study was registered at clinicaltrials.gov as NCT02761434.


Conceptualizing and Measuring Mental Illness Stigma: The Mental Illness Stigma Framework and Critical Review of Measures.
Although the last decade has seen a proliferation of research on mental illness stigma, lack of consistency and clarity in both the conceptualization and measurement of mental illness stigma has limited the accumulation of scientific knowledge about mental illness stigma and its consequences. In the present article, we bring together the different foci of mental illness stigma research with the Mental Illness Stigma Framework (MISF). The MISF provides a common framework and set of terminology for understanding mechanisms of mental illness stigma that are relevant to the study of both the stigmatized and the stigmatizer. We then apply this framework to systematically review and classify stigma measures used in the past decade according to their corresponding stigma mechanisms. We identified more than 400 measures of mental illness stigma, two thirds of which had not undergone any systematic psychometric evaluation. Stereotypes and discrimination received the most research attention, while mechanisms that focus on the perspective of individuals with mental illness (e.g., experienced, anticipated, or internalized stigma) have been the least studied. Finally, we use the MISF to discuss the strengths and weaknesses of mental illness stigma measurement, identify gaps in the literature, and provide recommendations for future research.


Neural-Network Vector Controller for Permanent-Magnet Synchronous Motor Drives: Simulated and Hardware-Validated Results.
This paper focuses on current control in a permanent-magnet synchronous motor (PMSM). This paper has two main objectives: the first objective is to develop a neural-network (NN) vector controller to overcome the decoupling inaccuracy problem associated with the conventional proportional-integral-based vector-control methods. The NN is developed using the full dynamic equation of a PMSM, and trained to implement optimal control based on approximate dynamic programming. The second objective is to evaluate the robust and adaptive performance of the NN controller against that of the conventional standard vector controller under motor parameter variation and dynamic control conditions by: 1) simulating the behavior of a PMSM typically used in realistic electric vehicle applications and 2) building an experimental system for hardware validation as well as combined hardware and simulation evaluation. The results demonstrate that the NN controller outperforms conventional vector controllers in both simulation and hardware implementation.


How flexible is the disulfide linker? A combined rotational-computational investigation of diallyl disulfide.
The symmetrically substituted diallyl disulfide adopts a non-symmetric conformation in the gas-phase, as observed with supersonic-jet rotational spectroscopy. The determination of the equilibrium structure with a predicate mixed regression illustrates both the benefits of the mass-dependent method for moderately large molecules and the structural peculiarities of the disulfide bridge.


Measures and time points relevant for post-surgical follow-up in patients with inflammatory arthritis: a pilot study.
Rheumatic diseases commonly affect joints and other structures in the hand. Surgery is a traditional way to treat hand problems in inflammatory rheumatic diseases with the purposes of pain relief, restore function and prevent progression. There are numerous measures to choose from, and a combination of outcome measures is recommended. This study evaluated if instruments commonly used in rheumatologic clinical practice are suitable to measure outcome of hand surgery and to identify time points relevant for follow-up. Thirty-one patients (median age 56 years, median disease duration 15 years) with inflammatory rheumatic disease and need for post-surgical occupational therapy intervention formed this pilot study group. Hand function was assessed regarding grip strength (Grippit), pain (VAS), range of motion (ROM) (Signals of Functional Impairment (SOFI)) and grip ability (Grip Ability Test (GAT)). Activities of daily life (ADL) were assessed by means of Disabilities of the Arm, Shoulder and Hand Outcome (DASH) and Canadian Occupational Performance Measure (COPM). The instruments were evaluated by responsiveness and feasibility; follow-up points were 0, 3, 6 and 12 months. All instruments showed significant change at one or more follow-up points. Satisfaction with activities (COPM) showed the best responsiveness (SMR>0.8), while ROM measured with SOFI had low responsiveness at most follow-up time points. The responsiveness of the instruments was stable between 6 and 12 month follow-up which imply that 6 month is an appropriate time for evaluating short-term effect of hand surgery in rheumatic diseases. We suggest a core set of instruments measuring pain, grip strength, grip ability, perceived symptoms and self-defined daily activities. This study has shown that VAS pain, the Grippit instrument, GAT, DASH symptom scale and COPM are suitable outcome instruments for hand surgery, while SOFI may be a more insensitive test. However, the feasibility of this protocol in clinical practice awaits prospective studies.


A neural circuit encoding sexual preference in humans.
Sexual preference determines mate choice for reproduction and hence guarantees conservation of species in mammals. Despite this fundamental role in human behavior, current knowledge on its target-specific neurofunctional substrate is based on lesion studies and therefore limited. We used meta-analytic remodeling of neuroimaging data from 364 human subjects with diverse sexual interests during sexual stimulation to quantify neural regions associated with sexual preference manipulations. We found that sexual preference is encoded by four phylogenetically old, subcortical brain structures. More specifically, sexual preference is controlled by the anterior and preoptic area of the hypothalamus, the anterior and mediodorsal thalamus, the septal area, and the perirhinal parahippocampus including the dentate gyrus. In contrast, sexual non-preference is regulated by the substantia innominata. We anticipate the identification of a core neural circuit for sexual preferences to be a starting point for further sophisticated investigations into the neural principles of sexual behavior and particularly of its aberrations.


Vitalum study design: RCT evaluating the efficacy of tailored print communication and telephone motivational interviewing on multiple health behaviors.
A large proportion of adults fail to meet public health guidelines for physical activity as well as fruit, vegetable and fat intake. Interventions are needed to improve these health behaviors. Both computer tailoring and motivational interviewing have shown themselves to be promising techniques for health behavior change. The Vitalum project aims to compare the efficacy of these techniques in improving the health behaviors of adults aged 45-70. This paper describes the design of the Vitalum study. Dutch general medical practices (N = 23) were recruited via a registration network or by personal invitation. The participants were then enrolled through these general practices using an invitational letter. They (n = 2,881) received a written baseline questionnaire to assess health behaviors, and potential psychosocial and socio-demographic behavioral determinants. A power analysis indicated that 1,600 participants who were failing to meet the guidelines for physical activity and either fruit or vegetable consumption were needed. Eligible participants were stratified based on hypertension status and randomized into one of four intervention groups: tailored print communication, telephone motivational interviewing, combined, and control. The first two groups either received four letters or took part in four interviews, whereas the combined group received two letters and took part in two interviews in turns at 5, 13, 30 and 43 weeks after returning the baseline questionnaire. Each letter and interview focused on physical activity or nutrition behavior. The participants also took part in a telephone survey 25 weeks after baseline to gather new information for tailoring. There were two follow-up questionnaires, at 47 and 73 weeks after baseline, to measure short- and long-term effects. The control group received a tailored letter after the last posttest. The process, efficacy and cost-effectiveness of the interventions will be examined by means of multilevel mixed regression, cost-effectiveness analyses and process evaluation. The Vitalum study simultaneously evaluates the efficacy of tailored print communication and telephone motivational interviewing, and their combined use for multiple behaviors and people with different motivational stages and education levels. The results can be used by policymakers to contribute to evidence-based prevention of chronic diseases. Dutch Trial Register NTR1068.


Content validity of the In-Hand Manipulation Test.
Object manipulation skills are a vital area for client assessment in occupational therapy, but in-hand manipulation skills are not specifically included in any standardized tests of hand function for children. The In-Hand Manipulation Test (IMT) was developed for use by occupational therapists with preschool and young school-age children. Assessment of the IMT's content validity was an important precursor to further development of the test. Twenty-four certified occupational therapists rated young children's performance during administration of the IMT before completing a content validity survey about the test. Overall, the IMT's content validity was supported by the feedback from the raters. A final test length of 50 items with two trials per item was considered acceptable, provided that the test takes no longer than 20 to 30 min to administer. The therapists were positive about the content and structure of the rating scale and the approach used in presenting activities to the children. Some issues related to functional validity of some skills or the proportions of in-hand manipulation skills were raised. Further development of the IMT for clinical and research use seems warranted. Revisions to the test will be made, and another pilot study will be conducted before normative data collection. Training for administering and scoring the test will incorporate the recommendations on the basis of this study's results.


Generation of electron beams carrying orbital angular momentum.
All forms of waves can contain phase singularities. In the case of optical waves, a light beam with a phase singularity carries orbital angular momentum, and such beams have found a range of applications in optical manipulation, quantum information and astronomy. Here we report the generation of an electron beam with a phase singularity propagating in free space, which we achieve by passing a plane electron wave through a spiral phase plate constructed naturally from a stack of graphite thin films. The interference pattern between the final beam and a plane electron wave in a transmission electron microscope shows the 'Y'-like defect pattern characteristic of a beam carrying a phase singularity with a topological charge equal to one. This fundamentally new electron degree of freedom could find application in a number of research areas, as is the case for polarized electron beams.


Structure and properties of the precursor/successor complex and transition state of the CrCl²⁺/Cr²⁺ electron self-exchange reaction via the inner-sphere pathway.
The electron self-exchange reaction CrCl(OH2)5(2+) + Cr(OH2)6(2+) → Cr(OH2)6(2+) + CrCl(OH2)5(2+), proceeding via the inner-sphere pathway, was investigated with quantum-chemical methods. Geometry and vibrational frequencies of the precursor/successor (P/S) complex, (H2O)5Cr(III)ClCr(II)(OH2)5(4+)/(H2O)5Cr(II)ClCr(III)(OH2)5(4+), and the transition state (TS), (H2O)5CrClCr(OH2)5(4+‡), were computed with density functional theory (DFT) and conductor polarizable continuum model hydration. Consistent data were obtained solely with long-range-corrected functionals, whereby in this study, LC-BOP was used. Bent and linear structures were computed for the TS and P/S. The electronic coupling matrix element (H(ab)) and the reorganizational energy (λ) were calculated with multistate extended general multiconfiguration quasi-degenerate second-order perturbation theory. The nuclear tunneling factor (Γ(n)), the nuclear frequency factor (ν(n)), the electronic frequency factor (ν(el)), the electron transmission coefficient (κ(el)), and the first-order rate constant (k(et)) for the electron-transfer step (the conversion of the precursor complex into the successor complex) were calculated based on the imaginary frequency (ν(‡)) of the TS, the Gibbs activation energy (ΔG(‡)), H(ab), and λ. The formation of the precursor complex via water substitution at Cr(OH2)6(2+) was also investigated with DFT and found to be very fast. Thus, the electron-transfer step is rate-determining. For the substitution reaction, only a bent TS structure could be obtained. The overall rate constant (k) was estimated as the product K(A)k(et), whereby K(A) is the equilibrium constant for the formation of the ion aggregate of the reactants Cr(OH2)6(2+) and CrCl(OH2)5(2+), Cr(H2O)6·CrCl(OH2)5(4+) (IAR). k calculated for the bent and linear isomers agrees with the experimental value.


The genome of the brown alga Ectocarpus siliculosus contains a series of viral DNA pieces, suggesting an ancient association with large dsDNA viruses.
Ectocarpus siliculosus virus-1 (EsV-1) is a lysogenic dsDNA virus belonging to the super family of nucleocytoplasmic large DNA viruses (NCLDV) that infect Ectocarpus siliculosus, a marine filamentous brown alga. Previous studies indicated that the viral genome is integrated into the host DNA. In order to find the integration sites of the viral genome, a genomic library from EsV-1-infected algae was screened using labelled EsV-1 DNA. Several fragments were isolated and some of them were sequenced and analyzed in detail. Analysis revealed that the algal genome is split by a copy of viral sequences that have a high identity to EsV-1 DNA sequences. These fragments are interspersed with DNA repeats, pseudogenes and genes coding for products involved in DNA replication, integration and transposition. Some of these gene products are not encoded by EsV-1 but are present in the genome of other members of the NCLDV family. Further analysis suggests that the Ectocarpus algal genome contains traces of the integration of a large dsDNA viral genome; this genome could be the ancestor of the extant NCLDV genomes. Furthermore, several lines of evidence indicate that the EsV-1 genome might have originated in these viral DNA pieces, implying the existence of a complex integration and recombination system. A protein similar to a new class of tyrosine recombinases might be a key enzyme of this system. Our results support the hypothesis that some dsDNA viruses are monophyletic and evolved principally through genome reduction. Moreover, we hypothesize that phaeoviruses have probably developed an original replication system.


Impact of mindfulness-based cognitive therapy on health care utilization: a population-based controlled comparison.
Elevated rates of mood and anxiety disorders among high utilizers of health care have been suggested as one driver of increased service use. We compared the impact of Mindfulness Based Cognitive Therapy (MBCT), a structured group treatment, on the rates of health care utilization with matched control participants receiving non-MBCT group therapy. Using Ontario health administrative data, we created a retrospective cohort of population-based patients receiving MBCT and an age- and gender-matched (3:1) cohort of non-MBCT group therapy controls. Subjects were recruited between 2003 and 2010 and stratified according to high/low rates of primary care utilization, with the high utilization cohort being the cohort of interest. The primary outcome was a reduction in an aggregate measure of non-mental health utilization comprising Emergency Department, non-mental health primary care, and non-psychiatrist specialist visits. There were 10,633 MBCT recipients, 4851 (46%) of whom were high utilizers. The proportion of high utilizers was 13,274 (45%, N=29,795) for non-MBCT group therapy controls. Among high utilizers, there was a significant reduction in non-mental health utilization among MBCT recipients compared to non-MBCT group therapy recipients (0.55 (0.21-0.89)) suggesting that for every two MBCT patients treated, there is a reduction in 1 non-mental health visit. Among high utilizers of primary care, MBCT reduced non-mental health care utilization 1year post-therapy compared to non-MBCT, group therapy controls. The reductions suggest that MBCT, an established treatment modality for a variety of mental illnesses, has the added benefit of reducing distress-related high health care utilization.


Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury.
Background Clinical trials in spinal cord injury (SCI) primarily rely on simplified outcome metrics (ie, speed, distance) to obtain a global surrogate for the complex alterations of gait control. However, these assessments lack sufficient sensitivity to identify specific patterns of underlying impairment and to target more specific treatment interventions. Objective To disentangle the differential control of gait patterns following SCI beyond measures of time and distance. Methods The gait of 22 individuals with motor-incomplete SCI and 21 healthy controls was assessed using a high-resolution 3-dimensional motion tracking system and complemented by clinical and electrophysiological evaluations applying unbiased multivariate analysis. Results Motor-incomplete SCI patients showed varying degrees of spinal cord integrity (spinal conductivity) with severe limitations in walking speed and altered gait patterns. Principal component (PC) analysis applied on all the collected data uncovered robust coherence between parameters related to walking speed, distortion of intralimb coordination, and spinal cord integrity, explaining 45% of outcome variance (PC 1). Distinct from the first PC, the modulation of gait-cycle variables (step length, gait-cycle phases, cadence; PC 2) remained normal with respect to regained walking speed, whereas hip and knee ranges of motion were distinctly altered with respect to walking speed (PC 3). Conclusions In motor-incomplete SCI, distinct clusters of discretely controlled gait parameters can be discerned that refine the evaluation of gait impairment beyond outcomes of walking speed and distance. These findings are specifically different from that in other neurological disorders (stroke, Parkinson) and are more discrete at targeting and disentangling the complex effects of interventions to improve walking outcome following motor-incomplete SCI.


Hormones and breast and endometrial cancers: preventive strategies and future research.
A number of hormonal approaches for prevention of endometrial and breast cancers have been proposed. Because of the hormonal responsiveness of both tumors, much attention has focused on effects of exogenous hormone use. Although estrogens in hormone replacement therapy increase the risk of endometrial cancer, the disease is substantially reduced by long-term use of oral contraceptives. The issues with breast cancer are more complex, mainly because of a variety of unresolved effects. Long-term estrogen use is associated with some increase in breast cancer risk, and certain patterns of oral contraceptives appear to predispose to early-onset disease. With respect to estrogens, preventive approaches for both tumors would include use for as limited periods of time as possible. Addition of a progestin appears to lower estrogen-associated endometrial disease, but its effect on breast cancer risk remains less clear. Additional studies on effects of detailed usage parameters should provide useful insights into etiologic mechanisms. Other preventive approaches for endometrial cancer that may work through hormonal mechanisms include staying thin, being physically active, and maintaining a vegetarian diet. Breast cancer risk may possibly be reduced by extended periods of breastfeeding, restriction of intake of alcoholic beverages, remaining thin later in life, and being physically active. Additional research is needed to clarify the biologic mechanisms of these associations. The bridging of epidemiology with the biologic sciences should clarify many unresolved issues and lead to better preventive approaches.


Local-distributed integration by a novel neuron ensures rapid initiation of animal locomotion.
Animals are adapted to respond quickly to threats in their environment. In many invertebrate and some vertebrate species, the evolutionary pressures have resulted in rapidly conducting giant axons, which allow short response times. Although neural circuits mediating escape behavior are identified in several species, little attention has been paid to this behavior in the medicinal leech, a model organism whose neuronal circuits are well known. We present data that suggest an alternative to giant axons for the rapid initiation of locomotion. A novel individual neuron, cell E21, appears to be one mediator of this short-latency action in the leech. In isolated nerve cord and semi-intact preparations, cell E21 excitation initiates and extends swimming and reduces the cycle period. The soma of this cell is located caudally, but its axon extends nearly the entire length of the nerve cord. We found that cell E21 fires impulses following local sensory inputs anywhere along the body and makes excitatory synapses onto the gating cells that drive swimming behavior. These distributed input-output sites minimize the distance information travels to initiate swimming behavior, thus minimizing the latency between sensory input and motor output. We propose that this single cell E21 functions to rapidly initiate or modulate locomotion through its distributed synaptic connections.


A polymorphism at position 400 in the connection subdomain of HIV-1 reverse transcriptase affects sensitivity to NNRTIs and RNaseH activity.
Reverse transcriptase (RT) plays an essential role in HIV-1 replication, and inhibition of this enzyme is a key component of HIV-treatment. However, the use of RT inhibitors can lead to the emergence of drug-resistant variants. Until recently, most clinically relevant resistance mutations were found in the polymerase domain of RT. Lately, an increasing number of resistance mutations has been identified in the connection and RNaseH domain. To further explore the role of these domains we analyzed the complete RT sequence of HIV-1 subtype B patients failing therapy. Position A/T400 in the connection subdomain is polymorphic, but the proportion of T400 increases from 41% in naïve patients to 72% in patients failing therapy. Previous studies suggested a role for threonine in conferring resistance to nucleoside RT inhibitors. Here we report that T400 also mediates resistance to non-nucleoside RT inhibitors. The susceptibility to NVP and EFV was reduced 5-fold and 2-fold, respectively, in the wild-type subtype B NL4.3 background. We show that substitution A400T reduces the RNaseH activity. The changes in enzyme activity are remarkable given the distance to both the polymerase and RNaseH active sites. Molecular dynamics simulations were performed, which provide a novel atomistic mechanism for the reduction in RNaseH activity induced by T400. Substitution A400T was found to change the conformation of the RNaseH primer grip region. Formation of an additional hydrogen bond between residue T400 and E396 may play a role in this structural change. The slower degradation of the viral RNA genome may provide more time for dissociation of the bound NNRTI from the stalled RT-template/primer complex, after which reverse transcription can resume.


The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase.
S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. We have determined the structures of S-adenosylmethionine decarboxylase complexed with the competitive inhibitors methylglyoxal bis(guanylhydrazone) and 4-amidinoindan-1-one-2'-amidinohydrazone as well as the irreversible inhibitors 5'-deoxy-5'-[N-methyl-N-[(2-aminooxy)ethyl]amino]adenosine, 5'-deoxy-5'-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine, and the methyl ester analogue of S-adenosylmethionine. These structures elucidate residues important for substrate binding and show how those residues interact with both covalently and noncovalently bound inhibitors. S-Adenosylmethionine decarboxylase has a four-layer alphabeta betaalpha sandwich fold with residues from both beta-sheets contributing to substrate and inhibitor binding. The side chains of conserved residues Phe7, Phe223, and Glu247 and the backbone carbonyl of Leu65 play important roles in binding and positioning the ligands. The catalytically important residues Cys82, Ser229, and His243 are positioned near the methionyl group of the substrate. One molecule of putrescine per monomer is observed between the two beta-sheets but far away from the active site. The activating effects of putrescine may be due to conformational changes in the enzyme, to electrostatic effects, or both. The adenosyl moiety of the bound ligand is observed in the unusual syn conformation. The five structures reported here provide a framework for interpretation of S-adenosylmethionine decarboxylase inhibition data and suggest strategies for the development of more potent and more specific inhibitors of S-adenosylmethionine decarboxylase.


High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome.
Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), triglycerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-ss(2)GPI) and C-reactive protein (CRP) from thrombotic PAPS (n = 34), thrombotic patients with inherited thrombophilia (IT; n = 36), subjects persistently positive for antiphospholipid antibodies (aPL, n = 18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n = 28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-ss(2)GPI and CRP. Average concentrations of HDL (p < 0.0001), LDL (p < 0.0001), CHO (p = 0.0002), ApoA-I (p = 0.002) were lower in PAPS whereas average TRY was higher (p = 0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p = 0.01) and IgG anti-ApoA-I (p < 0.0001) whereas the PAPS group showed greater average oxLDL-ss(2)GPI (p = 0.001) and CRP (p = 0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p = 0.004) and was an independent predictor of oxLDL-ss2GPI (p = 0.009). HDL and ApoA-I correlated negatively with CRP (p = 0.001 and p = 0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS.


Inflammatory myofibroblastic tumor of the bladder - an unexpected case coexisting with an ovarian teratoma.
Inflammatory myofibroblastic tumors (IMTs) mainly occur in children and young adults, usually in the first two decades of life. IMT-type tumors belong to neoplasms of an intermediate biologic potential with considerable rate of local recurrence and in some cases that able to create metastases. Presented case is the first IMT coexisting with the other neoplasm. In our paper we are going to present a peculiar case of an IMT of the bladder coexisting with an ovarian teratoma, and to discuss its pathogenesis, histological picture and differential diagnosis. A 19-year-old female was admitted to the Gynecological Department and during the surgery, two independent, non-adjacent tumors were found. To settle the diagnosis, a FISH examination with the ALK1 break apart probe was carried out. It confirmed the rearrangement of the chromosome 2p23. Morphologic and immunophenotypic similarities between an IMT and other malignant tumors of the bladder may lead to diagnostic errors and an unnecessary radical cystectomy as a result. The therapy of choice is only total excision of the tumor. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1937487606122622.


TRH1 encodes a potassium transporter required for tip growth in Arabidopsis root hairs.
Root hair initiation involves the formation of a bulge at the basal end of the trichoblast by localized diffuse growth. Tip growth occurs subsequently at this initiation site and is accompanied by the establishment of a polarized cytoplasmic organization. Arabidopsis plants homozygous for a complete loss-of-function tiny root hair 1 (trh1) mutation were generated by means of the T-DNA-tagging method. Trichoblasts of trh1 plants form initiation sites but fail to undergo tip growth. A predicted primary structure of TRH1 indicates that it belongs to the AtKT/AtKUP/HAK K(+) transporter family. The proposed function of TRH1 as a K(+) transporter was confirmed in (86)Rb uptake experiments, which demonstrated that trh1 plants are partially impaired in K(+) transport. In line with these results, TRH1 was able to complement the trk1 potassium transporter mutant of Saccharomyces, which is defective in high-affinity K(+) uptake. Surprisingly, the trh1 phenotype was not restored when mutant seedlings were grown at high external potassium concentrations. These data demonstrate that TRH1 mediates K(+) transport in Arabidopsis roots and is responsible for specific K(+) translocation, which is essential for root hair elongation.


Gut inflammation in chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis.Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut.If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.


The desmoplakin-intermediate filament linkage regulates cell mechanics.
The translation of mechanical forces into biochemical signals plays a central role in guiding normal physiological processes during tissue development and homeostasis. Interfering with this process contributes to cardiovascular disease, cancer progression, and inherited disorders. The actin-based cytoskeleton and its associated adherens junctions are well-established contributors to mechanosensing and transduction machinery; however, the role of the desmosome-intermediate filament (DSM-IF) network is poorly understood in this context. Because a force balance among different cytoskeletal systems is important to maintain normal tissue function, knowing the relative contributions of these structurally integrated systems to cell mechanics is critical. Here we modulated the interaction between DSMs and IFs using mutant forms of desmoplakin, the protein bridging these structures. Using micropillar arrays and atomic force microscopy, we demonstrate that strengthening the DSM-IF interaction increases cell-substrate and cell-cell forces and cell stiffness both in cell pairs and sheets of cells. In contrast, disrupting the interaction leads to a decrease in these forces. These alterations in cell mechanics are abrogated when the actin cytoskeleton is dismantled. These data suggest that the tissue-specific variability in DSM-IF network composition provides an opportunity to differentially regulate tissue mechanics by balancing and tuning forces among cytoskeletal systems.


A Multi-Stage Human Factors and Comfort Assessment of Instrumented Insoles Designed for Use in a Connected Health Infrastructure.
Wearable electronics are gaining widespread use as enabling technologies, monitoring human physical activity and behavior as part of connected health infrastructures. Attention to human factors and comfort of these devices can greatly positively influence user experience, with a subsequently higher likelihood of user acceptance and lower levels of device rejection. Here, we employ a human factors and comfort assessment methodology grounded in the principles of human-centered design to influence and enhance the design of an instrumented insole. A use case was developed and interrogated by stakeholders, experts, and end users, capturing the context of use and user characteristics for the instrumented insole. This use case informed all stages of the design process through two full design cycles, leading to the development of an initial version 1 and a later version 2 prototype. Each version of the prototype was subjected to an expert human factors inspection and controlled comfort assessment using human volunteers. Structured feedback from the first cycle of testing was the driver of design changes implemented in the version 2 prototype. This prototype was found to have significantly improved human factors and comfort characteristics over the first version of the prototype. Expert inspection found that many of the original problems in the first prototype had been resolved in the second prototype. Furthermore, a comfort assessment of this prototype with a group of young healthy adults showed it to be indistinguishable from their normal footwear. This study demonstrates the power and effectiveness of human factors and comfort assessment methodologies in influencing and improving the design of wearable devices.


On-the-Fly ab Initio Semiclassical Dynamics of Floppy Molecules: Absorption and Photoelectron Spectra of Ammonia.
We investigate the performance of on-the-fly ab initio (OTF-AI) semiclassical dynamics combined with the thawed Gaussian approximation (TGA) for computing vibrationally resolved absorption and photoelectron spectra. Ammonia is used as a prototype of floppy molecules, whose potential energy surfaces display strong anharmonicity. We show that despite complications due to the presence of large amplitude motion, the main features of the spectra are captured by the OTF-AI-TGA, which—by definition—does not require any a priori knowledge of the potential energy surface. Moreover, the computed spectra are significantly better than those based on the popular global harmonic approximation. Finally, we probe the limit of the TGA to describe higher-resolution spectra, where long time dynamics is required.


Associations of non-high density lipoprotein cholesterol and traditional blood lipid profiles with hyperuricemia among middle-aged and elderly Chinese people: a community-based cross-sectional study.
Increased serum uric acid (SUA) is associated with dyslipidemia. However, there are conflicting data about the role of single lipid species including non-high density lipoprotein cholesterol (non-HDL-C) in promoting SUA accumulation. Here, we aimed to compare non-HDL-C with other traditional blood lipid profiles in relation to hyperuricemia in a middle-aged and elderly Chinese population. Data was collected from 9580 participants undergoing routine physical examinations in Xiangcheng district of Suzhou. SUA, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were examined for all participants. Non-HDL-C was calculated by subtracting HDL-C from TC. The associations of blood lipid profiles with hyperuricemia were examined in men and women, respectively. The areas under Receiver Operating Characteristic (ROC) curves (AUCs) were compared to assess the discriminatory value of blood lipid parameters for predicting hyperuricemia. All blood lipid parameters significantly correlated with SUA (all P values <0.001). The correlation coefficient between SUA and TG was the highest in both genders. The correlation coefficient of non-HDL-C was higher than HDL-C in males and was higher than TC and LDL-C but followed HDL-C in females. In male group, AUC of TG (0.659) was greater than that of non-HDL-C (0.595) (P values <0.001). The AUC values of HDL-C, TC and LDL-C were lower; respectively 0.581, 0.559 and 0.552. In female group, AUC was highest for TG (0.678) followed by HDL-C (0.616), non-HDL-C (0.610), LDL-C (0.559) and TC (0.557) (all P values<0.001). In both genders, serum TG has the strongest association with hyperuricemia among blood lipid parameters. Non-HDL-C is also significantly associated with hyperuricemia.


Encoding of mixtures in a simple olfactory system.
Natural odors are usually mixtures; yet, humans and animals can experience them as unitary percepts. Olfaction also enables stimulus categorization and generalization. We studied how these computations are performed with the responses of 168 locust antennal lobe projection neurons (PNs) to varying mixtures of two monomolecular odors, and of 174 PNs and 209 mushroom body Kenyon cells (KCs) to mixtures of up to eight monomolecular odors. Single-PN responses showed strong hypoadditivity and population trajectories clustered by odor concentration and mixture similarity. KC responses were much sparser on average than those of PNs and often signaled the presence of single components in mixtures. Linear classifiers could read out the responses of both populations in single time bins to perform odor identification, categorization, and generalization. Our results suggest that odor representations in the mushroom body may result from competing optimization constraints to facilitate memorization (sparseness) while enabling identification, classification, and generalization.


Mental health of displaced and refugee children resettled in low-income and middle-income countries: risk and protective factors.
Children and adolescents who are forcibly displaced represent almost half the world's internally displaced and refugee populations. We undertook a two-part systematic search and review of the evidence-base for individual, family, community, and societal risk and protective factors for the mental health outcomes of children and adolescents. Here we review data for displacement to low-income and middle-income settings. We draw together the main findings from reports to identify important issues and establish recommendations for future work. We draw attention to exposure to violence as a well established risk factor for poor mental health. We note the paucity of research into predictor variables other than those in the individual domain and the neglect of other variables for the assessment of causal associations, including potential mediators and moderators identifiable in longitudinal work. We conclude with research and policy recommendations to guide the development and assessment of effective interventions.


Validation and Improvement of a Bicycle Crank Arm Based in Numerical Simulation and Uncertainty Quantification.
In this study, a finite element model of a bicycle crank arm are compared to experimental results. The structural integrity of the crank arm was analyzed in a universal dynamic test bench. The instrumentation used has allowed us to know the fatigue behavior of the component tested. For this, the prototype was instrumented with three rectangular strain gauge rosettes bonded in areas where failure was expected. With the measurements made by strain gauges and the forces registers from the load cell used, it has been possible to determine the state of the stresses for different loads and boundary conditions, which has subsequently been compared with a finite element model. The simulations show a good agreement with the experimental results, when the potential sources of uncertainties are considered in the validation process. This analysis allowed us to improve the original design, reducing its weight by 15%. The study allows us to identify the manufacturing process that requires the best metrological control to avoid premature crank failure. Finally, the numerical fatigue analysis carried out allows us to conclude that the new crank arm can satisfy the structural performance demanded by the international bicycle standard. Additionally, it can be suggested to the standard to include the verification that no permanent deformations have occurred in the crank arm during the fatigue test. It has been observed that, in some cases this bicycle component fulfils the minimum safety requirements, but presents areas with plastic strains, which if not taken into account can increase the risk of injury for the cyclist due to unexpected failure of the component.


Miniaturized magneto-optic sensor for pulsed magnetic field measurements.
The design and performance of a miniaturized magneto-optic probe using a terbium doped paramagnetic glass are described. The compactness and simplicity of the device are achieved by using the polarizer sheets obtained from a commonly available liquid crystal display. Plastic optical fibers are used to transport the light. A pulsed magnetic field up to 48 T has been generated and measured using high-voltage capacitor discharge in single-turn coils. A rise time and magnetic field-dependent anomalous behavior is observed in the terbium glass characteristics at room temperature.


Safety and feasibility of coronary stenting in unprotected left main coronary artery disease in the real world clinical practice--a single center experience.
This study evaluated the feasibility, safety, and prognostic outcome in patients with significant unprotected left main coronary artery (ULMCA) disease undergoing stenting. Between January 2010 and December 2012, totally 309 patients, including those with stable angina [13.9% (43/309)], unstable angina [59.2% (183/309)], acute non-ST-segment elevation myocardial infarction (NSTEMI) [24.3% (75/309)], and post-STEMI angina (i.e., onset of STEMI<7 days) [2.6% (8/309)] with significant ULMCA disease (>50%) undergoing stenting using transradial arterial approach, were consecutively enrolled. The patients' mean age was 68.9±10.8 yrs. Incidences of advance congestive heart failure (CHF) (defined as ≥ NYHA Fc 3) and multi-vessel disease were 16.5% (51/309) and 80.6% (249/309), respectively. Mechanical supports, including IABP for critical patients (defined as LVEF <35%, advanced CHF, or hemodynamically unstable) and extra-corporeal membrane oxygenator (ECMO) for hemodynamically collapsed patients, were utilized in 17.2% (53/309) and 2.6% (8/409) patients, respectively. Stent implantation was successfully performed in all patients. Thirty-day mortality rate was 4.5% (14/309) [cardiac death: 2.9% (9/309) vs. non-cardiac death: 1.6% (5/309)] without significant difference among four groups [2.3% (1) vs. 2.7% (5) vs. 9.3% (7) vs. 12.5% (1), p = 0.071]. Multivariate analysis identified acute kidney injury (AKI) as the strongest independent predictor of 30-day mortality (p<0.0001), while body mass index (BMI) and white blood cell (WBC) count were independently predictive of 30-day mortality (p = 0.003 and 0.012, respectively). Catheter-based LM stenting demonstrated high rates of procedural success and excellent 30-day clinical outcomes. AKI, BMI, and WBC count were significantly and independently predictive of 30-day mortality.


Human Strongyloidiasis in Hawaii: A Retrospective Review of Enzyme-Linked Immunosorbent Assay Serodiagnostic Testing.
Human strongyloidiasis is widely prevalent in tropical and subtropical regions worldwide but is not endemic in Hawaii. Subclinical, chronic infections may be lifelong; immunosuppressive therapy, particularly with glucocorticoids, may lead to serious or fatal disseminated disease, which is preventable. We performed a retrospective analysis of patients tested for Strongyloides immunoglobulin G antibody in an academic medical center in Honolulu, Hawaii, from 2005 to 2012. Of the 475 patients tested, 78 (16%) were seropositive. The largest proportion of seropositive cases was found among Micronesians (30%), Polynesians (26%), Filipinos (13%), and Southeast Asians (11%). Among the seropositive patients, the most likely reason for clinicians to order testing was blood eosinophilia. Stool parasite examination results were available for 58% of seropositive patients of which 11% were positive for Strongyloides stercoralis larvae. Antihelminthic therapy, usually ivermectin, was ordered for 71% of patients. After treatment, blood eosinophilia and Strongyloides serology results were reassessed for 76% and 35% of patients, respectively; both tests tended to show improvement. Travelers and immigrants from Strongyloides-endemic areas, including Micronesia and Polynesia, should have serodiagnostic testing for latent strongyloidiasis, and if positive, treated empirically with ivermectin, particularly when corticosteroids or other immunosuppressive therapies are anticipated.


Effects of early-life lactoferrin intervention on growth performance, small intestinal function and gut microbiota in suckling piglets.
The early postnatal stage is a critical period for suckling animals in developing intestinal function and stabilizing gut microbiota. Lactoferrin (LF) plays a critical role in promoting gut development and regulating gut microbiota. This study investigates the impact of early-life lactoferrin (LF) intervention on the growth performance, small intestinal function and gut microbiota in suckling piglets. Sixty suckling piglets (1.51 ± 0.05 kg) obtained from six sows (10 piglets per litter) were assigned to a control (CON) group and an LF group in each litter, which were sow-fed. Piglets in the LF group were orally administered 8-12 mL LF solution (0.5 g per kg body weight per day) for a week, and piglets in the CON group were orally administered the same dose of physiological saline. Six piglets (n = 6) from each group were euthanized on days 8 and 21. The early-life LF intervention increased growth performance, with higher villi height of the jejunum and greater disaccharidase activity of the jejunum and ileum (P < 0.05). Diarrhoea incidence decreased in the LF group from day 1 to day 7 (P < 0.05). Urinary lactulose-mannitol ratios decreased in the LF group, whereas the gene and protein expressions of jejunal occludin increased in the LF group on day 8 and day 21, and higher gene and protein levels of ileal occludin were observed on day 8 (P < 0.05). Additionally, the LF piglets had lower concentrations of IL-1β and TNF-α, and higher concentration of IL-10 in the jejunum (P < 0.05). For the ileum, higher concentration of IL-10 and lower concentration of TNF-α were observed in the LF group (P < 0.05). LF piglets had a greater abundance of Lactobacillus and lower abundance of Veillonella and Escherichia-Shigella in the jejunum on day 8 (P < 0.05). In the ileum, the abundance of Actinobacillus was decreased in the LF piglets on day 8 and day 21 (P < 0.05). The early-life LF intervention enhanced the growth performance and decreased diarrhoea incidence in the suckling piglets by promoting the development of intestinal function and changing the microbiota in the small intestine.


Biomarkers for Alzheimer's Disease in Saliva: A Systematic Review.
The histopathological changes of Alzheimer's disease (AD) are detectable decades prior to its clinical expression. However, there is a need for an early, inexpensive, noninvasive diagnostic biomarker to detect specific Alzheimer pathology. Recently developed neuroimaging biomarkers show promising results, but these methods are expensive and cause radiation. Furthermore, the analysis of cerebrospinal fluid (CSF) biomarkers requires an invasive lumbar puncture. Saliva is an easily obtained body fluid, and a stable saliva biomarker would therefore be a promising candidate for a future method for diagnosing AD. The purpose of this systematic review was to investigate studies of biomarkers in saliva samples for the diagnosis of AD. The included articles were identified through a literature search in PubMed and Google Scholar for all articles until November 1st, 2018, and furthermore, all reference lists of included articles were reviewed by hand. We included articles written in English investigating saliva from patients with AD and a control group. A total of 65 studies were identified, whereof 16 studies met the inclusion criteria and were included in the systematic review. A plethora of different biomarkers were investigated, and ten out of the sixteen studies showed a statistical significance in biomarkers between patients with AD and healthy, elderly controls, among these biomarkers for specific AD pathology (amyloid beta 1-42 (Aβ42) and tau). Aβ42 and tau seem to be worthy candidates for future salivary biomarkers for AD, but other biomarkers such as lactoferrin and selected metabolites also have potential. More studies must be carried out with larger sample sizes and a standardization of the sampling and processing method. Factors such as diurnal variation, AD patients' decreased ability of oral self-care, and salivary flowrates must be taken into consideration.


Assessing implementation mechanisms for an international agreement on research and development for health products.
The Member States of the World Health Organization (WHO) are currently debating the substance and form of an international agreement to improve the financing and coordination of research and development (R&D) for health products that meet the needs of developing countries. In addition to considering the content of any possible legal or political agreement, Member States may find it helpful to reflect on the full range of implementation mechanisms available to bring any agreement into effect. These include mechanisms for states to make commitments, administer activities, manage financial contributions, make subsequent decisions, monitor each other's performance and promote compliance. States can make binding or non-binding commitments through conventions, contracts, declarations or institutional reforms. States can administer activities to implement their agreements through international organizations, sub-agencies, joint ventures or self-organizing processes. Finances can be managed through specialized multilateral funds, financial institutions, membership organizations or coordinated self-management. Decisions can be made through unanimity, consensus, equal voting, modified voting or delegation. Oversight can be provided by peer review, expert review, self-reports or civil society. Together, states should select their preferred options across categories of implementation mechanisms, each of which has advantages and disadvantages. The challenge lies in choosing the most effective combinations of mechanisms for supporting an international agreement (or set of agreements) that achieves collective aspirations in a way and at a cost that are both sustainable and acceptable to those involved. In making these decisions, WHO's Member States can benefit from years of experience with these different mechanisms in health and its related sectors.


Making high-affinity T-cell receptors: a new class of targeted therapeutics.
The last two decades have seen the development of an expanding array of monoclonal antibodies, which are proving to be effective treatments for both cancer and autoimmune disease. A related protein, the human T-cell receptor (TCR), is able to access a new range of targets for which antibodies are unsuitable, and is being developed as a new class of protein therapeutics. Similar to antibodies, TCRs have a specific target and therefore a limited potential for side effects; however, a possible drawback with these receptors is that their natural affinity is low. This problem has recently been overcome using phage display to increase TCR affinity up to a million-fold.


Analysis of the possibility of analog detectors calibration by exploiting stimulated parametric down conversion.
Spontaneous parametric down conversion (SPDC) has been largely exploited as a tool for absolute calibration of photon-counting detectors, i.e detectors registering very small photon fluxes. In [J. Opt. Soc. Am. B 23, 2185 (2006)] we derived a method for absolute calibration of analog detectors using SPDC emission at higher photon fluxes, where the beam is seen as a continuum by the detector. Nevertheless intrinsic limitations appear when high-gain regime of SPDC is required to reach even larger photon fluxes. Here we show that stimulated parametric down conversion allow one to avoid this limitation, since stimulated photon fluxes are increased by the presence of the seed beam.


Gastric cancer: a case study in Turkey.
The aim of this study was to determine age-specific incidence ratios, gastric cancer localization trend, histologic subtype and cancer related survival that whether have changed during the period from 1999 to 2010. A total of 866 gastric cancer patients treated at the hospital were retrospectively evaluated. Categorical and continuous variables were summarized using descriptive statistics and were compared using the Chi-square and Mann-Whitney U-tests, respectively. Cancer related survival rates were estimated by the Kaplan-Meier method. The median age at diagnosis was 58 years. Trends concerning the median ages of the patients were increased (from 57 years to 59 years). The proportion of diffuse histological subtype gastric adenocarcinoma increased during the period from 1999 to 2010, and it was 27% between 1999 and 2002 and 32% between 2007 and 2010 (P = 0.04). The proportion of gastric adenocarcinoma localized in cardia increased during the period from 1999 to 2010, and was 7.2% between 1999 and 2002; and 22.5% in 2007 and 2010 (P = 0.004). For stage I that was diagnosed between 1999 and 2002, the relative survival was 67% and in patients diagnosed between 2007 and 2010 the rate was 85%. For stage II that was diagnosed between 1999 and 2002, the relative survival was 35% and in patients diagnosed between 2007 and 2010, the rate was 65%. Cox regression analysis was conducted based on age subgroup, diagnosis time, and gastric localization (proximal/distal) and for adenocarcinoma subtypes. Hazard ratio was 31.6 for stage IV (confidence interval [CI] = 10-42), 1.3 for cardia localization (CI = 1.04-1.6) and 1.37 for patients who had been diagnosed between 1999 and 2002 (1.14-1.78). The ratio of median age at diagnosis and proximal gastric adenocarcinoma, diffuse histologic subtype increased between 1999 and 2010. Cancer related survival significantly improved for stage I and stage II. Cardia localization and time of diagnosis between 1999 and 2002 had significantly poor outcome on relative survival.


Crystal structure and site 1 binding energetics of human placental lactogen.
In primates, placental lactogen (PL) is a pituitary hormone with fundamental roles during pregnancy involving fetal growth, metabolism, and stimulating lactation in the mother. Human placental lactogen (hPL) is highly conserved with human growth hormone (hGH) and both hormones bind to the hPRLR extracellular domain (ECD), the first step in receptor homodimerization, in a Zn2+-dependent manner. A modified surface plasmon resonance method was developed to measure the kinetics for hPL and hGH binding to the hPRLR ECD, with and without Zn2+ and showed that hPL has about a tenfold higher affinity for the hPRLR ECD1 than hGH. The crystal structure of the free state of hPL has been determined to 2.0 A resolution showing the molecule possesses an overall structure similar to other long chain four-helix bundle cytokines. Comparison of the free hPL structure with the 1:1 complex structure of hGH bound to the hPRLR ECD1 suggests that two surface loops undergo conformational changes >10 A upon binding. An 18 residue Ala-scan was used to characterize the binding energy epitope for the site 1 interface of hPL. Individual alanine substitutions at five positions reduced binding affinity by a DeltaDeltaG > or = 3 kcal mol(-1). A comparison of the hPL site 1 epitope with that previously determined for hGH indicates contributions of individual residues track reasonably well between hPL and hGH. In particular, residues involved in the zinc-binding site and Lys172 constitute the principal binding determinants for both hormones. However, several residues that are identical between hPL and hGH contribute quite differently to the binding of the hPRLR ECD1. Additionally, the overall magnitudes of the DeltaDeltaG changes observed from the Ala-scan of hPL were markedly larger than those determined in the comparative scan of hGH to the hPRLR ECD1. The structural and biophysical data presented here show that subtle changes in the structural context of an interaction can lead to significantly different effects at the individual residue level.


A systematic review of the efficacy of oral appliance design in the management of obstructive sleep apnoea.
Oral appliances (OAs) are increasingly advocated as a treatment option for obstructive sleep apnoea (OSA). However, it is unclear how their different design features influence treatment efficacy. The aim of this research was to systematically review the evidence on the efficacy of different OAs on polysomnographic indices of OSA. A MeSH and text word search were developed for Medline, Embase, Cinahl, and the Cochrane library. The initial search identified 1475 references, of which 116 related to studies comparing OAs with control appliances. Among those, 14 were randomized controlled trials (RCTs), which formed the basis of this review. The type of OA investigated in these trials was mandibular advancement devices (MADs), which were compared with either inactive appliances (six studies) or other types of MADs with different design features. Compared with inactive appliances, all MADs improved polysomnographic indices, suggesting that mandibular advancement is a crucial design feature of OA therapy for OSA. The evidence shows that there is no one MAD design that most effectively improves polysomnographic indices, but that efficacy depends on a number of factors including severity of OSA, materials and method of fabrication, type of MAD (monobloc/twin block), and the degree of protrusion (sagittal and vertical). These findings highlight the absence of a universal definition of treatment success. Future trials of MAD designs need to be assessed according to agreed success criteria in order to guide clinical practice as to which design of OAs may be the most effective in the treatment of OSA.