Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas.
This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection. Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update. We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting. We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.


Isotopic evidence for the provenance and turnover of organic carbon by soil microorganisms in the Antarctic dry valleys.
The extremely cold and arid Antarctic dry valleys are one of the most environmentally harsh terrestrial ecosystems supporting organisms in which the biogeochemical transformations of carbon are exclusively driven by microorganisms. The natural abundance of (13)C and (15)N in source organic materials and soils have been examined to obtain evidence for the provenance of the soil organic matter and the C loss as CO(2) during extended incubation (approximately 1200 days at 10 degrees C under moist conditions) has been used to determine the potential decay of soil organic C. The organic matter in soils remote from sources of liquid water or where lacustrine productivity was low had isotope signatures characteristic of endolithic (lichen) sources, whereas at more sheltered and productive sites, the organic matter in the soils that was a mixture mainly lacustrine detritus and moss-derived organic matter. Soil organic C declined by up to 42% during extended incubation under laboratory conditions (equivalent to 50-73 years in the field on a thermal time basis), indicating relatively fast turnover, consistent with previous studies indicating mean residence times for soil organic C in dry valley soils in the range 52-123 years and also with recent inputs of relatively labile source materials.


Analgesic and anti-inflammatory activities of fixed oil of Macrotyloma uniflorum (Lam.) Verdc. in mice and rats.
Macrotyloma uniflorum commonly known as horse gram or kulthi bean is grown as a pulse for livestock and human consumption. The beans contain about 1.3% fat, 18% protein, 15% carbohydrate along with vitamins and minerals. In traditional medicine it is used as antihyperglycemic, antioxidant, antihypertensive and diuretic. Other important medicinal uses include treatment of renal stones, obesity, piles, oedema and fever. The present study evaluated analgesic (by acetic acid induced writhing, hot plate and tail flick tests in mice) and anti-inflammatory (carrageenan induced paw edema in rats) activities of Macrotyloma uniflorum fixed oil (MUFO). Four groups were included in study: Group-I: Normal Saline Control (2ml/kg), Group-II: MUFO (2ml/kg), Group-III: MUFO (4ml/kg), and Group-IV: Standard Acetyl salicylic acid (ASA 300mg/kg). All results were significant however delayed onset of action was observed in tail flick and paw edema tests. Acute oral toxicity of the oil was also checked in mice and was found safe upto 4ml/kg dose, as no signs of toxicity and mortality were observed. It is concluded that Macrotyloma uniflorum fixed oil may possess analgesic and anti-inflammatory activity which can be related with a peripheral mechanism of action.


The effect of Hurricane Katrina: births in the U.S. Gulf Coast region, before and after the storm.
This report presents birth data for the region affected by Hurricane Katrina, which made landfall along the Gulf Coast of the United States on August 29, 2005, comparing the 12-month periods before and after the storm according to a wide variety of characteristics. Data are presented for maternal demographic characteristics including age, race, Hispanic origin, marital status, and educational attainment; medical care utilization by pregnant women (prenatal care and method of delivery); and infant characteristics or birth outcomes (period of gestation and birthweight). Descriptive tabulations of data reported on the birth certificates of residents of the 91 Federal Emergency Management Agency (FEMA)-designated counties and parishes of Alabama, Louisiana, and Mississippi are presented for the 12-month periods before and after Hurricane Katrina struck, from August 29, 2004, through August 28, 2006. Detailed data are shown separately for 14 selected, FEMA-designated coastal counties and parishes within a 100-mile radius of the Hurricane Katrina storm path, the area hit very hard by the storm and subsequent flooding. These 14 selected coastal counties and parishes are a subset of the 91 FEMA-designated counties and parishes. The total number of births in the 14 selected FEMA-designated counties and parishes decreased 19 percent in the 12 months after Hurricane Katrina compared with the 12 months before, with births declining in the selected counties and parishes of Louisiana and Mississippi and rising in the counties of Alabama. The number of births to non-Hispanic black women in the selected parishes of Louisiana fell substantially after Hurricane Katrina; births declined for non-Hispanic white, Hispanic, and Asian or Pacific Islander women in these selected parishes as well. The percentage of births to women under age 20 years for the selected counties and parishes after the storm was essentially unchanged in Alabama and Mississippi, but decreased in Louisiana. The proportion of births to unmarried women decreased in the selected parishes of Louisiana, but increased in the selected counties elsewhere. Large decreases were observed in very preterm and very low birthweight rates for the selected parishes of Louisiana following Hurricane Katrina, whereas a large increase was observed in very preterm births for the selected counties of Alabama.


Impact of socio-economic deprivation on death rates after surgery for upper gastrointestinal tract cancer.
We hypothesised that socio-economic deprivation in England may be a prognostic factor for death after oesophagectomy or gastrectomy for cancer of the upper gastrointestinal tract. We analysed statistical data from hospital records linked to death records for patients who underwent operations for oesophageal and gastric cancer in England from April 1998 to March 2002. The patients were stratified into quintiles according to the index of multiple deprivation (IMD) (2000) for their place (ward) of residence. Age and sex standardised death rates at 30 and 90 days for each deprivation quintile were calculated. Following oesophagectomy, death rates showed a significant association with IMD. They increased with increasing levels of deprivation: the odds ratio for death, comparing highest with lowest quintile for deprivation, was 1.37 (95% confidence interval 1.03-1.85) at 30 days and 1.30 (1.04-1.64) at 90 days. Following gastrectomy, the death rates showed smaller and nonsignificant associations with IMD with odds ratios of 1.16 (0.84-1.62) and 1.10 (0.86-1.41), respectively. There is a significant association between social deprivation and death after oesophagectomy, but less of an association, if any, after gastrectomy in current UK practice.


Freshly excavated fossil bones are best for amplification of ancient DNA.
Despite the enormous potential of analyses of ancient DNA for phylogeographic studies of past populations, the impact these analyses, most of which are performed with fossil samples from natural history museum collections, has been limited to some extent by the inefficient recovery of ancient genetic material. Here we show that the standard storage conditions and/or treatments of fossil bones in these collections can be detrimental to DNA survival. Using a quantitative paleogenetic analysis of 247 herbivore fossil bones up to 50,000 years old and originating from 60 different archeological and paleontological contexts, we demonstrate that freshly excavated and nontreated unwashed bones contain six times more DNA and yield twice as many authentic DNA sequences as bones treated with standard procedures. This effect was even more pronounced with bones from one Neolithic site, where only freshly excavated bones yielded results. Finally, we compared the DNA content in the fossil bones of one animal, a approximately 3,200-year-old aurochs, excavated in two separate seasons 57 years apart. Whereas the washed museum-stored fossil bones did not permit any DNA amplification, all recently excavated bones yielded authentic aurochs sequences. We established that during the 57 years when the aurochs bones were stored in a collection, at least as much amplifiable DNA was lost as during the previous 3,200 years of burial. This result calls for a revision of the postexcavation treatment of fossil bones to better preserve the genetic heritage of past life forms.


Self- and informant report of financial abilities in patients with Alzheimer's disease: reliable and valid?
To evaluate the consistency, stability, and accuracy of reports by patients with Alzheimer's disease (AD) and their caregivers regarding the patients' premorbid and current financial abilities. Consistency of reports was assessed within patient/caregiver dyads and within control/control informant dyads. Stability of reports over a 1-month interval was assessed for each group: patients with AD, caregivers, controls, and control informants. Accuracy of each group's reports was evaluated in reference to patients' and controls' performance on a direct psychometric measure of financial capacity. University medical center. Twenty patients with AD and 20 family caregivers; 23 controls and 23 family informants. The Prior Financial Capacity Form (PFCF) and the Current Financial Capacity Form (CFCF) were used. Parallel versions assessed self-report (patients, controls) and informant report (caregivers, control informants) at two visits 1 month apart. Patients with AD and controls were also administered the Financial Capacity Instrument (FCI), a direct assessment of the same abilities reported on the PFCF and CFCF. Patients with AD reported that they had more-intact current abilities than their caregivers reported. Patients with AD and their caregivers showed lower levels of stability over time on the PFCF and CFCF than did controls and their informants. Half of the patients with AD overestimated their current abilities relative to their FCI performance, whereas caregivers demonstrated both underestimation and overestimation errors. Controls and informants evidenced high levels of consistency, stability, and accuracy in PFCF and CFCF ratings. Patients with AD overestimate their financial abilities in comparison with the reports of their family caregivers. Both patients and caregivers' reports of patients' financial abilities showed limited stability and validity. The reliability and accuracy of self- and informant reports of financial abilities may be compromised in the context of dementia and caregiving, underscoring the need for direct assessment methods to augment self- and informant report in assessing functional decline in dementia.


Relationship Between Gastric Emptying and Diurnal Glycemic Control in Type 1 Diabetes Mellitus: A Randomized Trial.
In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia. To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control. This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center. GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study. These were GE and continuous glucose monitoring (CGM). The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study. In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.


Chemokine signaling mediated monocyte infiltration affects anxiety-like behavior following blast injury.
The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2RFP/+: CX3CR1GFP/+ mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4 h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1β were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1β leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.


Evolution of 1500-m Olympic Running Performance.
This study determined the evolution of performance and pacing for each winner of the men's Olympic 1500-m running track final from 1924 to 2020. Data were obtained from publicly available sources. When official splits were unavailable, times from sources such as YouTube were included and interpolated from video records. Final times, lap splits, and position in the peloton were included. The data are presented relative to 0 to 400 m, 400 to 800 m, 800 to 1200 m, and 1200 to 1500 m. Critical speed and D' were calculated using athletes' season's best times. Performance improved ∼25 seconds from 1924 to 2020, with most improvement (∼19 s) occurring in the first 10 finals. However, only 2 performances were world records, and only one runner won the event twice. Pacing evolved from a fast start-slow middle-fast finish pattern (reverse J-shaped) to a slower start with steady acceleration in the second half (J-shaped). The coefficient of variation for lap speeds ranged from 1.4% to 15.3%, consistent with a highly tactical pacing pattern. With few exceptions, the eventual winners were near the front throughout, although rarely in the leading position. There is evidence of a general increase in both critical speed and D' that parallels performance. An evolution in the pacing pattern occurred across several "eras" in the history of Olympic 1500-m racing, consistent with better trained athletes and improved technology. There has been a consistent tactical approach of following opponents until the latter stages, and athletes should develop tactical flexibility, related to their critical speed and D', in planning prerace strategy.


In-depth protein profiling of the postsynaptic density from mouse hippocampus using data-independent acquisition proteomics.
Located at neuronal terminals, the postsynaptic density (PSD) is a highly complex network of cytoskeletal scaffolding and signaling proteins responsible for the transduction and modulation of glutamatergic signaling between neurons. Using ion-mobility enhanced data-independent label-free LC-MS/MS, we established a reference proteome of crude synaptosomes, synaptic junctions, and PSD derived from mouse hippocampus including TOP3-based absolute quantification values for identified proteins. The final dataset across all fractions comprised 49 491 peptides corresponding to 4558 protein groups. Of these, 2102 protein groups were identified in highly purified PSD in at least two biological replicates. Identified proteins play pivotal roles in neurological and synaptic processes providing a rich resource for studies on hippocampal PSD function as well as on the pathogenesis of neuropsychiatric disorders. All MS data have been deposited in the ProteomeXchange with identifier PXD000590 (http://proteomecentral.proteomexchange.org/dataset/PXD000590).


Development of a loop-mediated isothermal amplification (LAMP) and a direct LAMP for the specific detection of Nosema ceranae, a parasite of honey bees.
Nosema ceranae is a ubiquitous microsporidian pathogen infecting the midgut of honey bees. The infection causes bee nosemosis, a disease associated with malnutrition, dysentery, and lethargic behavior, and results in considerable economic losses in apiculture. The use of a rapid, sensitive, and inexpensive DNA-based molecular detection method assists in the surveillance and eventual control of this pathogen. To this end, a loop-mediated isothermal amplification (LAMP) assay targeting the single-copy gene encoding the polar tube protein 3 (PTP3) has been developed. Genomic DNA of N. ceranae-infected forager bees sampled from distant geographic regions could be reliably amplified using the established LAMP assay. The N. ceranae-LAMP showed higher sensitivity than a classical reference PCR (98.6 vs 95.7%), when both approaches were applied to the detection of N. ceranae. LAMP detected a ten-fold lower infection rate than the reference PCR (1 pg vs 10 pg genomic DNA, respectively). In addition, we show highly specific and sensitive detection of N. ceranae from spore preparations in a direct LAMP format. No cross-reactions with genomic DNA and/or spores from N. apis, often co-infecting A. mellifera, or from N. bombi, infecting bumble bees, were observed. This low-cost and time-saving molecular detection method can be easily applied in simple laboratory settings, facilitating a rapid detection of N. ceranae in honey bees in epidemiological studies, surveillance and control, as well as evaluation of therapeutic measures against nosemosis.


Post-diagnosis dietary factors and survival after invasive breast cancer.
Little is known about the effects of diet after breast cancer diagnosis on survival. We prospectively examined the relation between post-diagnosis dietary factors and breast cancer and all-cause survival in women with a history of invasive breast cancer diagnosed between 1987 and 1999 (at ages 20-79 years). Diet after breast cancer diagnosis was measured using a 126-item food frequency questionnaire. Among 4,441 women without a history of breast cancer recurrence prior to completing the questionnaire, 137 subsequently died from breast cancer within 7 years of enrollment. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for intake of macronutrients as well as selected micronutrients and food groups from Cox proportional hazards regression models. After adjustment for factors at diagnosis (age, state of residence, menopausal status, smoking, breast cancer stage, alcohol, history of hormone replacement therapy), interval between diagnosis and diet assessment, and at follow-up (energy intake, breast cancer treatment, body mass index, and physical activity), women in the highest compared to lowest quintile of intake of saturated fat and trans fat had a significantly higher risk of dying from any cause (HR = 1.41, 95% CI = 1.06-1.87, P trend = 0.03) for saturated fat; (HR = 1.78, 95% CI = 1.35-2.32, P trend = 0.01) for trans fat intake. Associations were similar, though did not achieve statistical significance, for breast cancer survival. This study suggests that lower intake of saturated and trans fat in the post-diagnosis diet is associated with improved survival after breast cancer diagnosis.


Interferometry of strongly refracting axisymmetric phase objects.
Inversion of measurements of optical pathlength through strongly refracting, radially symmetric phase objects, such as plasmas, is discussed. An exact inversion scheme, based upon methods originally applied in seismology is developed and applied to interferometry. It is shown that Abel inversion, which assumes that the probing rays are straight lines, yields rather accurate results if the interferogram is formed with appropriate imaging.


Thickness sorting of two-dimensional transition metal dichalcogenides via copolymer-assisted density gradient ultracentrifugation.
Two-dimensional transition metal dichalcogenides have emerged as leading successors to graphene due to their diverse properties, which depend sensitively on sample thickness. Although solution-based exfoliation methods hold promise for scalable production of these materials, existing techniques introduce irreversible structural defects and/or lack sufficient control over the sample thickness. In contrast, previous work on carbon nanotubes and graphene has shown that isopycnic density gradient ultracentrifugation can produce structurally and electronically monodisperse nanomaterial populations. However, this approach cannot be directly applied to transition metal dichalcogenides due to their high intrinsic buoyant densities when encapsulated with ionic small molecule surfactants. Here, we overcome this limitation and thus demonstrate thickness sorting of pristine molybdenum disulfide (MoS2) by employing a block copolymer dispersant composed of a central hydrophobic unit flanked by hydrophilic chains that effectively reduces the overall buoyant density in aqueous solution. The resulting solution-processed monolayer MoS2 samples exhibit strong photoluminescence without further chemical treatment.


Autonomic nerve activity and atrial fibrillation.
This review focuses on the importance of autonomic nervous system (ANS) activity in the induction of paroxysmal atrial fibrillation (PAF). Clinical studies suggest that both sympathetic and parasympathetic nervous systems are important in mediating PAF. Consistent with that hypothesis, heart rate variability analyses showed that sympathovagal imbalance is present before the onset of PAF episodes. The importance of the ANS in PAF is further supported by animal experiments and recent clinical studies showing that vagal denervation enhances the efficacy of circumferential pulmonary vein ablation in preventing AF recurrence. In vitro studies show that ANS activation facilitates early afterdepolarization and triggered activity by simultaneously prolonging the intracellular calcium (Ca(i)) transient (sympathetic effect) and shortening the action potential duration (parasympathetic effect). By simultaneously mapping the membrane potential and Ca(i) transient in canine pulmonary vein during sympathetic stimulation, we demonstrated that spontaneous (voltage-independent) sarcoplasmic reticulum calcium release underlies the mechanisms of focal discharges. We developed and studied canine models of PAF induced by electrical, structural, and neural remodeling. We also have developed methods for long-term continuous recording of sympathetic and vagal nerve activity in ambulatory dogs. Preliminary results show that simultaneous sympathovagal discharges precede the onset of PAF in these dogs. ANS activity and Ca(i) transient dynamics are important in the development of PAF. These studies suggest that new methods or drugs aimed at modification of cardiac ANS activity may lead to new opportunities for AF control.


System-based strategy for the management of meconium aspiration syndrome: 198 consecutive cases observations.
To evaluate whether the system-based strategy for management of meconium aspiration syndrome (MAS) could reduce the morbidity and mortality rate of MAS in our institute, a prospective consecutive clinical observation was conducted. System-based strategy including appropriately trained the relevant medical staff to familiar with neonatal resuscitation program, early surfactant replacement or lavage following with high-frequency ventilator (HFV) and/or inhaled nitric oxide (iNO). Outcome measurements were the morbidity and mortality rates of MAS. All infants of MAS in the study period were included except cases of congenital malformations or cyanotic congenital heart disease (CHD). Oxygen, nasal continuous positive airway pressure (CPAP), and intermittent mandatory ventilation (IMV) were applied as clinically indicated. Surfactant was used as replacement or lavage therapy for MAS infants whose oxygen index (OI) exceeded 20 or value for AaDO2 exceeded 400 within 6 hours of age. High-frequency oscillator ventilation (HFO) was applied for infants of MAS that demonstrated intractable respiratory failure with conventional mechanical ventilation and 100% oxygen. Inhaled nitric oxide (iNO) was used with IMV or HFO for infants of persistent pulmonary hypertension (PPHN) when it was unresponsive to conventional therapy. Dexamethasone was prescribed in infants of severe hypotension that did not respond to dopamine and epinephrine. A series of 198 consecutive infants of MAS born in this hospital during 9 years were analyzed. There was no mortality. Fourteen infants developed PPHN, 11 had pneumothorax, 1 had pulmonary hemorrhage, 2 had neurologic sequelae because of severe asphyxia, and 2 developed bronchopulmonary dysplasia. Our results indicated that appropriately trained relevant medical staff with neonatal resuscitation program to avoid complicated MAS and early surfactant replacement or lavage following with HFO and/or iNO could reduce the morbidity and mortality rate of MAS even without extracorporeal membrane oxygenation (ECMO).


Dietary and psych predictors of weight loss after gastric bypass.
Identifying severely obese patients who will succeed after bariatric surgery remains challenging. Although numerous studies have attempted to identify preoperative patient characteristics associated with weight loss, the roles of many dietary and psychological characteristics are unclear. The purpose of this study was to examine preoperative dietary and psychological predictors of successful weight loss after bariatric surgery. This retrospective cohort study included all patients who underwent laparoscopic Roux-en-Y gastric bypass from September 2011-June 2013 at a single institution (n = 124). Patient demographics, comorbidities, dietary and psychological factors, and weight loss outcomes were extracted from the electronic medical record. Bivariate associations between these factors and successful weight loss (≥50% excess body weight) were examined. Factors significant at P ≤ 0.1 were included in a multivariate logistic regression model. On bivariate analysis, absence of either type 2 diabetes or hypertension, preoperative weight <270 lbs, no intentional past weight loss >50 lbs, no previous purging or family history of obesity, and no soda consumption preoperatively were associated with successful weight loss (P < 0.1). On multivariate analysis, successful weight loss was inversely associated with the presence of type 2 diabetes (odds ratio [OR], 0.22, 95% confidence interval [CI], 0.06-0.73), maximum intentional past weight loss >50 lbs (OR, 0.12 [95% CI, 0.04-0.43]), and decreasing soda consumption by >50% (OR, 0.27 [95% CI, 0.08-0.99]). Patients with type 2 diabetes mellitus, significant previous weight loss, and poor soda consumption habits are more likely to experience suboptimal weight loss after bariatric surgery. Additional preoperative counseling and close postoperative follow-up is warranted for these patients.


Critical review and meta-analysis of spurious hemolysis in blood samples collected from intravenous catheters.
A number of preanalytical activities strongly influence sample quality, especially those related to sample collection. Since blood drawing through intravenous catheters is reported as a potential source of erythrocyte injury, we performed a critical review and meta-analysis about the risk of catheter-related hemolysis. We performed a systematic search on PubMed, Web of Science and Scopus to estimate the risk of spurious hemolysis in blood samples collected from intravenous catheters. A meta-analysis with calculation of Odds ratio (OR) and Relative risk (RR) along with 95% Confidence interval (95% CI) was carried out using random effect mode. Fifteen articles including 17 studies were finally selected. The total number of patients was 14,796 in 13 studies assessing catheter and evacuated tubes versus straight needle and evacuated tubes, and 1251 in 4 studies assessing catheter and evacuated tubes versus catheter and manual aspiration. A significant risk of hemolysis was found in studies assessing catheter and evacuated tubes versus straight needle and evacuated tubes (random effect OR 3.4; 95% CI = 2.9-3.9 and random effect RR 1.07; 95% CI = 1.06-1.08), as well as in studies assessing catheter and evacuated tubes versus catheter and manual aspiration of blood (OR 3.7; 95% CI = 2.7-5.1 and RR 1.32; 95% CI = 1.24-1.40). Sample collection through intravenous catheters is associated with significant higher risk of spurious hemolysis as compared with standard blood drawn by straight needle, and this risk is further amplified when intravenous catheter are associated with primary evacuated blood tubes as compared with manual aspiration.


Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP.
The centromere is responsible for accurate chromosome segregation. Mammalian centromeres are specified epigenetically, with all active centromeres containing centromere-specific chromatin in which CENP-A replaces histone H3 within the nucleosome. The proteins responsible for assembly of human CENP-A into centromeric nucleosomes during the G1 phase of the cell cycle are shown here to be distinct from the chromatin assembly factors previously shown to load other histone H3 variants. Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.


Synergy in efficacy of fungal entomopathogens and permethrin against West African insecticide-resistant Anopheles gambiae mosquitoes.
Increasing incidences of insecticide resistance in malaria vectors are threatening the sustainable use of contemporary chemical vector control measures. Fungal entomopathogens provide a possible additional tool for the control of insecticide-resistant malaria mosquitoes. This study investigated the compatibility of the pyrethroid insecticide permethrin and two mosquito-pathogenic fungi, Beauveria bassiana and Metarhizium anisopliae, against a laboratory colony and field population of West African insecticide-resistant Anopheles gambiae s.s. mosquitoes. A range of fungus-insecticide combinations was used to test effects of timing and sequence of exposure. Both the laboratory-reared and field-collected mosquitoes were highly resistant to permethrin but susceptible to B. bassiana and M. anisopliae infection, inducing 100% mortality within nine days. Combinations of insecticide and fungus showed synergistic effects on mosquito survival. Fungal infection increased permethrin-induced mortality rates in wild An. gambiae s.s. mosquitoes and reciprocally, exposure to permethrin increased subsequent fungal-induced mortality rates in both colonies. Simultaneous co-exposure induced the highest mortality; up to 70.3+/-2% for a combined Beauveria and permethrin exposure within a time range of one gonotrophic cycle (4 days). Combining fungi and permethrin induced a higher impact on mosquito survival than the use of these control agents alone. The observed synergism in efficacy shows the potential for integrated fungus-insecticide control measures to dramatically reduce malaria transmission and enable control at more moderate levels of coverage even in areas where insecticide resistance has rendered pyrethroids essentially ineffective.


Anti-Ro antibodies and complete heart block in adults with Sjögren's syndrome.
There are emerging case reports worldwide of complete heart block in adults who test positive for anti-Ro antibodies and the underlying primary Sjögren's syndrome (pSS). The association between fetal/congenital cardiac abnormalities and transplacental transfer of anti-Ro antibodies is well established; there is, however, an ongoing debate about the underlying mechanism of activity of these antibodies in the cardiac tissue. In the past, maternal cardiac tissue was believed to be resistant to these pathogenic effects. This case highlights the need to change our understanding of how these antibodies cause adverse arrhythmogenic cardiac effects in adults. We present the case of a 44-year-old female with pSS and positive anti-Ro autoantibodies, who was diagnosed with autoimmune-induced complete heart block after presenting with dizziness and palpitations. She required insertion of a permanent cardiac pacemaker and has made a full recovery. Although the arrhythmogenic effects are rare, it may be that cardiac conduction in adults is not as resistant to anti-Ro antibodies as proposed.


Group cognitive behavioural therapy for insomnia: Effects on sleep and depressive symptomatology in a sample with comorbidity.
To investigate the effects of group CBT for insomnia (CBT-I) on insomnia and depressive symptomatology in a comorbid sample through a randomised controlled trial with a 6 month follow-up. 64 participants were recruited through advertisements and randomised to receive CBT-I or an active control (relaxation training: RT) during four group sessions. Insomnia Severity Index and BDI-II were the primary outcome measures, assessed pre-treatment, post-treatment and at 6 month follow-up. Insomnia and depressive diagnoses, and functional impairment were assessed before and after treatment, whereas sleep diary data was gathered continuously from one week before treatment until after treatment. CBT-I was more efficient than RT in reducing insomnia severity and equally effective in reducing depressive symptoms, although CBT-I was associated with a higher proportion of remitted persons than RT, regarding both insomnia and depression diagnoses. Also, CBT-I was associated with less functional impairment, shorter sleep onset latency and wake after sleep onset but both treatments had equal improvements of sleep quality, early morning awakenings and total sleep time. Group CBT-I is an efficient form of insomnia-treatment for people with insomnia comorbid with depressive symptomatology. The mixed results regarding depression outcomes warrants replication and further studies into treatment mechanisms.


Effect of glutathione on the cadmium chelation of EDTA in a patient with cadmium intoxication.
In order to evaluate the efficiency and renal protective effects of glutathione during Ca(++)-EDTA chelation therapy for chronic cadmium intoxication, we measured the renal excretion of cadmium, β(2)-microglobulin, proteinuria, and hematuria during intravenous administration of glutathione with Ca(++)-EDTA in a 54-year-old patient with chronic cadmium intoxication. We administered 500 mg of Ca(++)-EDTA and 50 mg/kg of glutathione alone or in 1 L of normal saline over the next 24 hours and repeated this over 12 consecutive days. During the first 3 days, the basal levels (only saline administration) were determined; during the second 3 days, Ca(++)-EDTA only was administered, for the third sequence of 3 days, Ca(++)-EDTA with glutathione was provided, and for the last 3 days, glutathione alone was given. One month later, the same protocol was repeated. There were six blood and urine samples to analyze in each group. The blood cadmium level was higher when the EDTA was infused together with glutathione (7.44 ± 0.73 µg/L, p < 0.01) compared to the basal level of 4.6 ± 0.44 µg/L. Also, the renal cadmium excretion was significantly higher in the EDTA with glutathione group than in the basal group (23.4 ± 15.81 µg/g creatinine vs 89.23 ± 58.52 µg/g creatinine, p < 0.01). There was no difference in the protein/creatinine and β(2)-microglobulin/creatinine ratio in the urine (p > 0.05) among the groups. Furthermore, microhematuria and proteinuria did not develop over the observation period of 6 months. These results suggest that glutathione administration with EDTA might be an effective treatment modality for patients with cadmium intoxication.


Hybrid Improper Ferroelectricity in (Sr,Ca)3Sn2O7 and Beyond: Universal Relationship between Ferroelectric Transition Temperature and Tolerance Factor in n = 2 Ruddlesden-Popper Phases.
Hybrid improper ferroelectricity, which utilizes nonpolar but ubiquitous rotational/tilting distortions to create polarization, offers an attractive route to the discovery of new ferroelectric and multiferroic materials because its activity derives from geometric rather than electronic origins. Design approaches blending group theory and first principles can be utilized to explore the crystal symmetries of ferroelectric ground states, but in general, they do not make accurate predictions for some important parameters of ferroelectrics, such as Curie temperature ( TC). Here, we establish a predictive and quantitative relationship between TC and the Goldschmidt tolerance factor, t, by employing n = 2 Ruddlesden-Popper (RP) A3B2O7 as a prototypical example of hybrid improper ferroelectrics. The focus is placed on an RP system, (Sr1- xCa x)3Sn2O7 ( x = 0, 0.1, and 0.2), which allows for the investigation of the purely geometric (ionic size) effect on ferroelectric transitions, due to the absence of the second-order Jahn-Teller active (d0 and 6s2) cations that often lead to ferroelectric distortions through electronic mechanisms. We observe a ferroelectric-to-paraelectric transition with TC = 410 K for Sr3Sn2O7. We also find that the TC increases linearly up to 800 K upon increasing the Ca2+ content, i.e., upon decreasing the value of t. Remarkably, this linear relationship is applicable to the suite of all known A3B2O7 hybrid improper ferroelectrics, indicating that the TC correlates with the simple crystal chemistry descriptor, t, based on the ionic size mismatch. This study provides a predictive guideline for estimating the TC of a given material, which would complement the convergent group-theoretical and first-principles design approach.


The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments.
The role of the kidney in the catabolism of Bence Jones proteins, intact IgG molecules, and isolated L chains, Fab and Fc fragments of IgG, was studied. The proteins were purified, radioiodinated, and their survival times measured in nephrectomized, ureter-severed, and control mice. Active endogenous catabolism was the major factor in overall Bence Jones metabolism since excretion as proteinuria accounted for less than 25% of the total metabolism. The survival times of lambda- and kappa-type human Bence Jones proteins and the Bence Jones protein produced by mice with MPC-2 plasma cell tumor were exceedingly short in both unoperated and ureter-severed mice, with 50% of the injected protein catabolized in from 0.8-1.6 hr. In contrast, the survival of Bence Jones protein was markedly prolonged in nephrectomized animals, with 50% of the injected dose catabolized in from 9 to 17 hr. This ten-fold decrease in catabolic rate indicates that the kidneys are the major site of breakdown of Bence Jones proteins. Similar studies with other proteins indicated that the kidneys are also the major site for catabolism of isolated L chains but not of intact IgG molecules. The Fc immunoglobulin fragment was not catabolized and the Fab fragment only partially catabolized by the kidney. When ureter-severed animals were allowed to develop advanced uremia before being studied, the survival of Bence Jones protein was greatly prolonged, indicating that the catabolic process is impaired in the presence of uremia. The nature of this renal catabolism remains unknown. These observations suggest that the Bence Jones proteins and L chains observed in the urine of patients may reflect only a small fraction of such molecules synthesized by these patients. Furthermore, they provide an explanation for the prolongation of Bence Jones protein survival and the development of Bence Jones proteinemia observed in subjects with multiple myeloma and impaired renal function.


Toward a more uniform sampling of human genetic diversity: a survey of worldwide populations by high-density genotyping.
High-throughput genotyping data are useful for making inferences about human evolutionary history. However, the populations sampled to date are unevenly distributed, and some areas (e.g., South and Central Asia) have rarely been sampled in large-scale studies. To assess human genetic variation more evenly, we sampled 296 individuals from 13 worldwide populations that are not covered by previous studies. By combining these samples with a data set from our laboratory and the HapMap II samples, we assembled a final dataset of ~250,000 SNPs in 850 individuals from 40 populations. With more uniform sampling, the estimate of global genetic differentiation (F(ST)) substantially decreases from ~16% with the HapMap II samples to ~11%. A panel of copy number variations typed in the same populations shows patterns of diversity similar to the SNP data, with highest diversity in African populations. This unique sample collection also permits new inferences about human evolutionary history. The comparison of haplotype variation among populations supports a single out-of-Africa migration event and suggests that the founding population of Eurasia may have been relatively large but isolated from Africans for a period of time. We also found a substantial affinity between populations from central Asia (Kyrgyzstani and Mongolian Buryat) and America, suggesting a central Asian contribution to New World founder populations.


Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling.
Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 ( approximately 10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.


People-centred integrated care in urban China.
In most countries, the demand for integrated care for people with chronic diseases is increasing as the population ages. This demand requires a fundamental shift of health-care systems towards more integrated service delivery models. To achieve this shift in China, the World Health Organization, the World Bank and the Chinese government proposed a tiered health-care delivery system in accordance with a people-centred integrated care model. The approach was pioneered in Luohu district of Shenzhen city from 2015 to 2017 as a template for practice. In September 2017, China's health ministry introduced this approach to people-centred integrated care to the entire country. We describe the features of the Luohu model in relation to the core action areas and implementation strategies proposed and we summarize data from an evaluation of the first two years of the programme. We discuss the challenges faced during implementation and the lessons learnt from it for other health-care systems. We consider how to improve collaboration between institutions, how to change the population's behaviour about using community health services as the first point of contact and how to manage resources effectively to avoid budget deficits. Finally, we outline next steps of the Luohu model and its potential application to strengthen health care in other urban health-care systems.


Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.


Modulation of angiotensin II-mediated cardiac remodeling by the MEF2A target gene Xirp2.
The vasoactive peptide angiotensin II (Ang II) is a potent cardiotoxic hormone whose actions have been well studied, yet questions remain pertaining to the downstream factors that mediate its effects in cardiomyocytes. The in vivo role of the myocyte enhancer factor (MEF)2A target gene Xirp2 in Ang II-mediated cardiac remodeling was investigated. Here we demonstrate that the MEF2A target gene Xirp2 (also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart. Xirp2 belongs to the evolutionarily conserved, muscle-specific, actin-binding Xin gene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized the Xirp2 promoter and demonstrate that Ang II activates Xirp2 expression by stimulating MEF2A transcriptional activity. To further characterize the role of Xirp2 downstream of Ang II signaling we generated mice harboring a hypomorphic allele of the Xirp2 gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adult Xirp2 hypomorphic mice displayed cardiac hypertrophy and increased beta myosin heavy chain expression. Strikingly, Xirp2 hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis. These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart.


Osteoarthritis year 2013 in review: clinical.
Some major themes over the past year in clinical research of osteoarthritis (OA) include obesity, muscle strength, pain mechanisms, novel disease modifying drugs, and risk factors for poor outcomes of joint replacement surgery. A systematic literature search was performed using PubMed from January 2012 to December 2012. The articles selected for this review represent topics the authors thought best highlight recent clinical OA research.


A Stevedore's protein knot.
Protein knots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Seven distinctly knotted folds have already been identified. It is by and large unclear how these exceptional structures actually fold, and only recently, experiments and simulations have begun to shed some light on this issue. In checking the new protein structures submitted to the Protein Data Bank, we encountered the most complex and the smallest knots to date: A recently uncovered alpha-haloacid dehalogenase structure contains a knot with six crossings, a so-called Stevedore knot, in a projection onto a plane. The smallest protein knot is present in an as yet unclassified protein fragment that consists of only 92 amino acids. The topological complexity of the Stevedore knot presents a puzzle as to how it could possibly fold. To unravel this enigma, we performed folding simulations with a structure-based coarse-grained model and uncovered a possible mechanism by which the knot forms in a single loop flip.


Association Between Pancreatitis and Immune-mediated Haemolytic Anaemia in Cats: A Cross-sectional Study.
In most cases, the underlying causes of feline pancreatitis and feline immune-mediated haemolytic anaemia (IMHA) remain unknown. Following the observation that some cats present with both diseases concurrently, the aim of this cross-sectional study was to investigate if the two disorders were associated statistically in this species. A residency case log of all cases seen at the Small Animal Hospital, University of Glasgow, Glasgow, UK, between July 2004 and December 2007, was used as the database for this study and an association between these two disorders was assessed by Fisher's exact test. Of the 155 sick cats included in the study, nine were diagnosed at the time of presentation with pancreatitis (prevalence of 5.8%) and 11 with IMHA (prevalence of 7.1%). In three of these cats both conditions were present concurrently at the time of presentation (prevalence of 1.9%). A significant association between these two disease was found (Odds Risk 8.63, exact 95% confidence interval 1.15-49.31, P = 0.0178). Two possible biological explanations for the statistical association found between these two diseases are that one of these conditions may represent the cause for the onset of the other or that an underlying disorder of the immune system may concurrently target feline red blood cells and the exocrine pancreas.


Histidine-rich glycoprotein possesses antioxidant activity through self-oxidation and inhibition of hydroxyl radical production via chelating divalent metal ions in Fenton's reaction.
Sepsis is caused by infections associated with life-threatening multiple organ failure (MOF). Septic MOF appears to be closely related to circulatory failure due to immunothrombosis. This process involves the production of reactive oxygen spices (ROS) in inflammatory sites. Therefore, the detoxification of the systemic excess ROS is important for the improvement of the process in septic pathogenesis. Histidine-rich glycoprotein (HRG), a plasma glycoprotein, ameliorates a septic condition through the suppression of both excess ROS production from neutrophils and immunothrombosis. Hydroxyl radical is known as the most important species among ROS in pathogenesis; however, the direct influence of HRG on hydroxyl radical formation and ROS activity is poorly understood. In this study, we showed that HRG, in a concentration-dependent manner, efficiently inhibited the production of hydroxyl radical induced by the Fenton's reaction through chelation of the divalent iron. HRG also exhibited antioxidant activity against peroxyl radical by oxidation of HRG itself as a substrate; however, it did not show superoxide dismutase and catalase-like activities. Additionally, HRG enhanced glutathione peroxidase, a well-known antioxidant enzyme, activity. These results suggest that HRG may play a unique role in suppression of the production of hydroxyl radicals and subsequent tissue damage at inflammatory sites. Marked reduction in plasma HRG in sepsis might lose such an important protective mechanism. Thus, the present study provides evidence that inhibition of ROS and ROS-production systems by HRG may contribute to antiseptic effects in vivo and that HRG could be potential therapy for ROS-related diseases.


Breast cancer patients have improved immune and neuroendocrine functions following massage therapy.
Women with breast cancer are at risk for elevated depression, anxiety, and decreased natural killer (NK) cell number. Stress has been linked to increased tumor development by decreasing NK cell activity. The objectives of this study included examining massage therapy for women with breast cancer for (1) improving mood and biological measures associated with mood enhancement (serotonin, dopamine), (2) reducing stress and stress hormone levels, and (3) boosting immune measures. Thirty-four women (M age=53) diagnosed with Stage 1 or 2 breast cancer were randomly assigned postsurgery to a massage therapy group (to receive 30-min massages three times per week for 5 weeks) or a control group. The massage consisted of stroking, squeezing, and stretching techniques to the head, arms, legs/feet, and back. On the first and last day of the study, the women were assessed on (1) immediate effects measures of anxiety, depressed mood, and vigor and (2) longer term effects on depression, anxiety and hostility, functioning, body image, and avoidant versus intrusive coping style, in addition to urinary catecholamines (norepinephrine, epinephrine, and dopamine) and serotonin levels. A subset of 27 women (n=15 massage) had blood drawn to assay immune measures. The immediate massage therapy effects included reduced anxiety, depressed mood, and anger. The longer term massage effects included reduced depression and hostility and increased urinary dopamine, serotonin values, NK cell number, and lymphocytes. Women with Stage 1 and 2 breast cancer may benefit from thrice-weekly massage therapy for reducing depressed mood, anxiety, and anger and for enhancing dopamine, serotonin, and NK cell number and lymphocytes.


Uterine torsion mimicking supine hypotension syndrome after regional anaesthesia.
A 40-year-old gravida 5 para2 +2 was admitted at 38 weeks +5 days of gestation for elective caesarean section in view of unstable lie. After spinal anaesthesia, when the patient was positioned supine for caesarean section, she developed acute onset breathlessness and dizziness. Blood pressure was unrecordable. She remained symptomatic with hypotension and bradycardia despite lateral tilt and intravenous atropine. On entering the peritoneal cavity, a congested uterus with torsion in a clockwise direction to almost 180° with the posterior wall facing anteriorly was noted. Immediate attempt to detort the uterus was successful. The patient immediately became symptomatically better and the uterine congestion resolved. Uterine incision was given in the anterior lower segment delivering a healthy baby. High index of suspicion and detorsion of the uterus avoided the inadvertent incision in the congested posterior uterine wall which could have resulted in massive postpartum haemorrhage.


Science and technology roadmap for graphene, related two-dimensional crystals, and hybrid systems.
We present the science and technology roadmap for graphene, related two-dimensional crystals, and hybrid systems, targeting an evolution in technology, that might lead to impacts and benefits reaching into most areas of society. This roadmap was developed within the framework of the European Graphene Flagship and outlines the main targets and research areas as best understood at the start of this ambitious project. We provide an overview of the key aspects of graphene and related materials (GRMs), ranging from fundamental research challenges to a variety of applications in a large number of sectors, highlighting the steps necessary to take GRMs from a state of raw potential to a point where they might revolutionize multiple industries. We also define an extensive list of acronyms in an effort to standardize the nomenclature in this emerging field.


Recombinant peanut allergen Ara h I expression and IgE binding in patients with peanut hypersensitivity.
Peanut allergy is a significant health problem because of the frequency, the potential severity, and the chronicity of the allergic sensitivity. Serum IgE from patients with documented peanut hypersensitivity reactions and a peanut cDNA expression library were used to identify clones that encode peanut allergens. One of the major peanut allergens, Ara h I, was selected from these clones using Ara h I specific oligonucleotides and polymerase chain reaction technology. The Ara h I clone identified a 2.3-kb mRNA species on a Northern blot containing peanut poly (A)+ RNA. DNA sequence analysis of the cloned inserts revealed that the Ara h I allergen has significant homology with the vicilin seed storage protein family found in most higher plants. The isolation of the Ara h I clones allowed the synthesis of this protein in E. coli cells and subsequent recognition of this recombinant protein in immunoblot analysis using serum IgE from patients with peanut hypersensitivity. With the production of the recombinant peanut protein it will now be possible to address the pathophysiologic and immunologic mechanisms regarding peanut hypersensitivity reactions specifically and food hypersensitivity in general


The threat of veterinary medicinal products and biocides on pollinators: A One Health perspective.
The One Health approach acknowledges that human health is firmly linked to animal and environmental health. It involves using animals such as bees and other pollinators as sentinels for environmental contamination or biological indicators. Beekeepers noticed intoxications of apiaries located in the vicinity of sheep and cattle farms, which led to the suspicion of bees' intoxication by the products used for livestock: veterinary medicinal products (VMPs) and Biocides, confirmed by laboratory analysis. We review the legal context of VMPs and Biocidal products considering Europe as a case study, and identify shortcomings at the environmental level. We describe the possible ways these products could intoxicate bees in the vicinity of livestock farms. We also illustrate the way they may impact non-target species. The cases of ivermectin and abamectin as VMPs, deltamethrin and permethrin as Biocides are considered as case studies. We show bees can be exposed to new and unrecognized routes of exposure to these chemicals, and demonstrate that their application in livestock farming can affect the survival of pollinators, such as bees. We conclude that: (1) figures on the marketing/use of these chemicals should be harmonized, centralized and publicly available, (2) research should be devoted to clarifying how pollinators are exposed to VMPs and Biocides, (3) toxicity studies on bees should be carried out, and (4) pollinators should be considered as non-targeted species concerning the environmental risk assessment before their marketing authorization. We propose the term "Multi-use substances" for active ingredients with versatile use.


Uncrowded Hypervolume-Based Multiobjective Optimization with Gene-Pool Optimal Mixing.
Domination-based multiobjective (MO) evolutionary algorithms (EAs) are today arguably the most frequently used type of MOEA. These methods, however, stagnate when the majority of the population becomes nondominated, preventing further convergence to the Pareto set. Hypervolume-based MO optimization has shown promising results to overcome this. Direct use of the hypervolume, however, results in no selection pressure for dominated solutions. The recently introduced Sofomore framework overcomes this by solving multiple interleaved single-objective dynamic problems that iteratively improve a single approximation set, based on the uncrowded hypervolume improvement (UHVI). It thereby however loses many advantages of population-based MO optimization, such as handling multimodality. Here, we reformulate the UHVI as a quality measure for approximation sets, called the uncrowded hypervolume (UHV), which can be used to directly solve MO optimization problems with a single-objective optimizer. We use the state-of-the-art gene-pool optimal mixing evolutionary algorithm (GOMEA) that is capable of efficiently exploiting the intrinsically available grey-box properties of this problem. The resulting algorithm, UHV-GOMEA, is compared with Sofomore equipped with GOMEA, and the domination-based MO-GOMEA. In doing so, we investigate in which scenarios either domination-based or hypervolume-based methods are preferred. Finally, we construct a simple hybrid approach that combines MO-GOMEA with UHV-GOMEA and outperforms both.


Populating decision-analytic models: the feasibility and efficiency of database searching for individual parameters.
The aim of the study was to investigate the feasibility and effectiveness of searching selected databases to identify information required to populate a decision-analytic model. Methods of searching for information to populate a decision-analytic model were piloted using a case study of prophylactic antibiotics to prevent recurrent urinary tract infections in children. This study explored how the information requirements for a decision-analytic model could be developed into searchable questions and how search strategies could be derived to answer these questions. The study also assessed the usefulness of three published search filters and explored which resources might produce relevant information for the various model parameters. Based on the data requirements for this case study, 42 questions were developed for searching. These questions related to baseline event rates, health-related quality of life and outcomes, relative treatment effects, resource use and unit costs, and antibiotic resistance. A total of 1,237 records were assessed by the modeler, and of these, 48 were found to be relevant to the model. Search precision ranged from 0 percent to 38 percent, and no single database proved the most useful for all the questions. The process of conducting specific searches to address each of the model questions provided information that was useful in populating the case study model. The most appropriate resources to search were dependent on the question, and multiple database searching using focused search strategies may prove more effective in finding relevant data than thorough searches of a single database.


Activated platelets contribute importantly to myocardial reperfusion injury.
Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice (P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment (P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.


Safety and outcome of percutaneous nephrolithotomy in patients with solitary kidney: A tertiary care center experience.
Percutaneous nephrolithotomy (PCNL) for stones in solitary kidney poses a significant challenge and potential threat for acute kidney injury or progression of chronic kidney disease (CKD). We present our experience of PCNL in solitary functioning kidney (SFK) to evaluate the safety, efficacy, and postoperative complications and highlight the differences between these outcomes with respect to the stage of CKD. We carried out a retrospective study of patients with SFK, who underwent PCNL at our center from April 2010 to March 2018. Patients who had a minimum of 6 months of follow-up were included. Patients were classified into CKD groups based on the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. Group 1 included Stages 1, 2, and 3A and Group 2 included Stages 3B, 4, and 5. Postoperative complications and stone-free rate were recorded and graded according to the Clavien-Dindo classification and compared between the two groups. We had a total of 128 patients (Group 1 - 84 and Group 2 - 44). Stone-free rate after the first PCNL was higher in Group 1 as compared to Group 2 (88.1% [n = 74] vs. 50% [n = 22], P = 0.02). Overall, 48 patients (37.5%) had postoperative complications, but most were minor. Clavien Grade 1 and 2 complications were seen in 34 patients (Group 1, n = 18 and Group 2, n = 16, P = 0.069), whereas Grade 3 and 4 complications were seen in 14 patients (Group 1, n = 2 and Group 2, n = 12, P < 0.001), respectively. Need for postoperative (number of sessions) dialysis was seen with increased frequency in patients with higher chronic kidney stages (Group 1 vs. Group 2; 6 vs. 22 sessions, P < 0.001). PCNL in SFK is safe, with satisfactory outcome, but patients with advanced CKD stage have higher risk of complications including need for dialysis and may require multiple sessions for complete stone clearance. Hence, they should be managed at high output tertiary centers.


Same-day antimicrobial susceptibility test using acoustic-enhanced flow cytometry visualized with supervised machine learning.
Purpose. Antimicrobial susceptibility is slow to determine, taking several days to fully impact treatment. This proof-of-concept study assessed the feasibility of using machine-learning techniques for analysis of data produced by the flow cytometer-assisted antimicrobial susceptibility test (FAST) method we developed.Methods. We used machine learning to assess the effect of antimicrobial agents on bacteria, comparing FAST results with broth microdilution (BMD) antimicrobial susceptibility tests (ASTs). We used Escherichia coli (1), Klebsiella pneumoniae (1) and Staphylococcus aureus (2) strains to develop the machine-learning algorithm, an expanded panel including these plus E. coli (2), K. pneumoniae (3), Proteus mirabilis (1), Pseudomonas aeruginosa (1), S. aureus (2) and Enterococcus faecalis (1), tested against FAST and BMD (Sensititre, Oxoid), then two representative isolates directly from blood cultures.Results. Our data machines defined an antibiotic-unexposed population (AUP) of bacteria, classified the FAST result by antimicrobial concentration range, and determined a concentration-dependent antimicrobial effect (CDE) to establish a predicted inhibitory concentration (PIC). Reference strains of E. coli, K. pneumoniae and S. aureus tested with different antimicrobial agents demonstrated concordance between BMD results and machine-learning analysis (CA, categoric agreement of 91 %; EA, essential agreement of 100 %). CA was achieved in 35 (83 %) and EA in 28 (67 %) by machine learning on first pass in a challenge panel of 27 Gram-negative and 15 Gram-positive ASTs. Same-day AST results were obtained from clinical E. coli (1) and S. aureus (1) isolates.Conclusions. The combination of machine learning with the FAST method generated same-day AST results and has the potential to aid early antimicrobial treatment decisions, stewardship and detection of resistance.


Distribution of methylene blue after injection into the epidural space of anaesthetized pregnant and non-pregnant sheep.
The aim of the study was to determine the distribution of different volumes of methylene blue solution injected into the epidural space in anaesthetized pregnant and non-pregnant sheep, to evaluate its cranial distribution and to compare between them. Fifteen pregnant and fifteen non-pregnant sheep were included in the study. Sheep were anaesthetized and received 0.05, 0.1, or 0.2 mL/kg of a lumbosacral epidural solution containing 0.12% methylene blue in 0.9% saline. Thirty minutes after the epidural injection, the ewes were euthanized. The extension of the dye within the epidural space was measured, and the correlation between the volume of the dye injected and the number of stained vertebrae was evaluated. The cranial migration of the dye between pregnant and non-pregnant sheep was also compared. The results show that the volume of methylene blue injected epidurally into pregnant and non-pregnant sheep correlated directly with its cephalic distribution into the epidural space; and a volume of 0.1 mL/kg or 0.2 mL/kg stained up to the first lumbar segment in pregnant and non-pregnant sheep, respectively. Also, the results suggest that the volume of drugs administered into the epidural space of pregnant sheep should be half the volume that would be used in non-pregnant sheep.


The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition.
Xanthohumol (Xan) is a natural constituent of human nutrition. Little is known about its actions on leishmanial parasites and their mitochondria as putative target. Therefore, we determined the antileishmanial activity of Xan and resveratrol (Res, as alternative compound with antileishmanial activity) with respect to mitochondria in Leishmania amazonensis promastigotes/amastigotes (LaP/LaA) in comparison with their activity in peritoneal macrophages from mouse (PMM) and macrophage cell line J774A.1 (J774). Mechanistic studies were conducted in Leishmania tarentolae promastigotes (LtP) and mitochondrial fractions isolated from LtP. Xan and Res demonstrated antileishmanial activity in LaA [half inhibitory concentration (IC50): Xan 7 µ m, Res 14 µ m]; while they had less influence on the viability of PMM (IC50: Xan 70 µ m, Res >438 µ m). In contrast to Res, Xan strongly inhibited oxygen consumption in Leishmania (LtP) but not in J774 cells. This was based on the inhibition of the mitochondrial electron transfer complex II/III by Xan, which was less pronounced with Res. Neither Xan nor Res increased mitochondrial superoxide release in LtP, while both decreased the mitochondrial membrane potential in LtP. Bioenergetic studies showed that LtP mitochondria have no spare respiratory capacity in contrast to mitochondria in J774 cells and can therefore much less adapt to stress by mitochondrial inhibitors, such as Xan. These data show that Xan may have antileishmanial activity, which is mediated by mitochondrial inhibition.


Analysis of mutations and alternative splicing patterns in the CFTR gene using mRNA derived from nasal epithelial cells.
Ten to fifteen percent of CF chromosomes carry mutations which are not detected by routine screening of the CFTR gene for known mutations. Many techniques have been used to screen the CFTR gene for these remaining mutations. Most of the methods use genomic DNA, and since the CFTR gene contains 27 exons, are necessarily labour intensive. We have screened the entire coding region of CFTR, by chemical cleavage of 7 overlapping segments of amplified cDNA. Using this method we have identified 4 sequence changes which had not been detected by screening genomic DNA, and successfully detected 10 out of 13 known mutations. In addition, we have identified 8 alternatively spliced forms of CFTR mRNA, 4 of which have not been described previously. These include transcripts lacking a) exon 3, b) exons 2 + 3, c) exons 9 + 12, and d) the final 357 bp of exon 15 as a result of use of the cryptic splice donor site CA2863/GTTCGT).


The ethics of circumcision of male infants.
Infant circumcision has recently attracted controversy with professional groups recommending it and various individuals trying to criminalize it. Circumcision is beneficial in the prevention of certain diseases, causing minimal tangible harm to those circumcised. This article argues that government should affirmatively adopt policies tolerating minority practices. Such activities should be banned only if they cause substantial damage to society or its members, or if they engender risks or injuries to which no reasonable person would consent. The benefits and risks of circumcision are outlined. Circumcision of male infants does not trigger cause for government to abolish it, and should be permitted if parents desire it. This article also summarizes common arguments against circumcision and attempts to refute them. These arguments are based on a desire for gender equality as well as a belief that minors should not undergo elective bodily alteration. If there are no unusual risks, parents can ethically authorize, and physicians ethically perform, elective infant circumcision for prophylaxis of disease, ritual purposes, or aesthetic reasons. Furthermore, the state should permit this.


Antibiotic-Associated Adverse Events in Hospitalized Children.
Antibiotic-associated adverse events (AEs) in hospitalized children have not been comprehensively characterized. We conducted a retrospective observational study of children hospitalized at The Johns Hopkins Hospital receiving ≥24 hours of systemic antibiotics. Consensus regarding antibiotic-associated AE definitions was established by 5 infectious diseases specialists prior to data collection. Two physicians reviewed potential AEs and determined whether they were more likely than not related to antibiotics after comprehensive manual chart review. Inpatient and post-discharge AEs were identified using the Epic Care Everywhere network. AEs evaluated from the initiation of antibiotics until 30 days after antibiotic completion included gastrointestinal, hematologic, hepatobiliary, renal, neurologic, dermatologic, cardiac, myositis, vascular access device-related events, and systemic reactions. Ninety-day AEs included Clostridioides difficile infections, multidrug-resistant organism infections, and clinically significant candidal infections. The impact of AEs was categorized as necessitating additional diagnostic testing, changes in medications, unplanned medical encounters, prolonged or new hospitalizations, or death. Among 400 antibiotic courses, 21% were complicated by at least one AE and 30% occurred post-discharge. Each additional day of antibiotics was associated with a 7% increased odds of an AE. Of courses complicated by an AE, 66% required further intervention. Hematologic, gastrointestinal, and renal AEs were the most common, accounting for 31%, 15%, and 11% of AEs, respectively. AEs complicated 35%, 35%, 19%, and 18% of courses of piperacillin-tazobactam, tobramycin, ceftazidime, and vancomycin, respectively. More than 1 in 5 courses of antibiotics administered to hospitalized children are complicated by AEs. Clinicians should weigh the risk of harm against expected benefit when prescribing antibiotics.


Communication: angular momentum alignment and fluorescence polarization of alkali atoms photodetached from helium nanodroplets.
The theory of photofragments angular momentum polarization is applied to the photodetachment of an electronically excited alkali atom from a helium nanocluster (N = 200). The alignment of the electronic angular momentum of the bare excited alkali atoms produced is calculated quantum mechanically by solving the excited states coupled equations with potentials determined by density functional theory (DFT). Pronounced oscillations as a function of excitation energy are predicted for the case of Na@(He)200, in marked contrast with the absorption cross-section and angular distribution of the ejected atoms which are smooth functions of the energy. These oscillations are due to quantum interference between different coherently excited photodetachment pathways. Experimentally, these oscillations should be reflected in the fluorescence polarization and polarization-resolved photoelectron yield of the ejected atoms, which are proportional to the electronic angular momentum alignment. In addition, this result is much more general than the test case of NaHe200 studied here. It should be observable for larger droplets, for higher excited electronic states, and for other alkali as well as for alkali-earth atoms. Detection of these oscillations would show that the widely used pseudo-diatomic model can be valid beyond the prediction of absorption spectra and could help in interpreting parts of the dynamics, as already hinted by some experimental results on angular anisotropy of bare alkali fragments.


AN EXPERIMENTAL STUDY OF OXALURIA, WITH SPECIAL REFERENCE TO ITS FERMENTATIVE ORIGIN.
1. As varying amounts of calcium oxalate may be held in solution in the urine, conclusions based upon the presence or number of calcium oxalate crystals found therein are of no real value as an indication of the quantity of oxalic acid present. 2. Unless the utmost care is exercised, the results obtained by quantitative estimation of oxalic acid are subject to large percentages of error. This is especially true in the use of Neubauer's or Shultzen's methods, in which the calcium oxalate is precipitated in an alkaline solution. 3. An ordinary mixed diet regularly contains traces of oxalic acid or its salts. 4. A portion of the oxalic acid ingested with the food may be absorbed and reappear unchanged in the urine. 5. The normal daily excretion of oxalic acid in the urine fluctuates with the amount taken in the food, and varies from a few milligrammes to two or three centigrammes, being usually below ten milligrammes. 6. In health, no oxalic acid, or only a trace, is formed in the body, but that present in the urine has been ingested with the food. 7. In certain clinical disturbances which in some of the cases studied above were associated with absence of free hydrochloric acid from the gastric juice, oxalic acid is formed in the organism. 8. This formation in the organism is connected with fermentative activity in the alimentary canal. (a) The prolonged feeding of dogs with excessive quantities of glucose, together with meat, leads eventually to a state of oxaluria. (6) This experimental oxaluria is associated with a mucous gastritis, and with absence of free hydrochloric acid in the gastric contents. (c) The oxaluria and the accompanying gastritis are referable to fermentation induced by the excessive feeding with sugar. (d) The experimental gastritis from fermentation is associated with the formation of oxalic acid in the gastric contents. 9. The symptoms attributed to an oxalic acid diathesis, with the exception of those due to local irritation in the genitourinary tract, do not appear to be due to the presence in the system of soluble oxalates, but are more likely to depend on other products of fermentation and putrefaction.


The Swedish Two-County Trial of mammographic screening: cluster randomisation and end point evaluation.
The Swedish Two-County Trial has been criticised on the grounds of the cluster randomisation and alleged bias in classification of cause of death. In the Two-County Trial, 77 080 women were randomised to regular invitation to screening (active study population, ASP) and 55 985 to no invitation (passive study population, PSP), in 45 geographical clusters. After approximately 7 years, the PSP was invited to screening and the trial closed. We analysed data using hierarchical statistical models to take account of cluster randomisation, and performed a conservative analysis assuming a systematic difference between ASP and PSP in baseline breast cancer mortality in one of the counties. We also analysed deaths from causes other than breast cancer and from all causes among breast cancer cases diagnosed in the ASP and PSP. Taking account of the cluster randomisation there was a significant 30% reduction in breast cancer mortality in the ASP. Conservatively, assuming a systematic difference between ASP and PSP clusters in baseline breast cancer mortality, there was a significant 27% reduction in mortality in the ASP. Ignoring classification of cause of death, there was a significant 13% reduction in all-cause mortality in breast cancer cases in the ASP. Breast cancer mortality is a valid end point and mammographic screening does indeed reduce mortality from breast cancer. The criticisms of the Swedish Two-County Trial are unfounded.


Biomineralization of Schlumbergerella floresiana, a significant carbonate-producing benthic foraminifer.
Most foraminifera that produce a shell are efficient biomineralizers. We analyzed the calcitic shell of the large tropical benthic foraminifer Schlumbergerella floresiana. We found a suite of macromolecules containing many charged and polar amino acids and glycine that are also abundant in biomineralization proteins of other phyla. As neither genomic nor transcriptomic data are available for foraminiferal biomineralization yet, de novo-generated sequences, obtained from organic matrices submitted to ms blast database search, led to the characterization of 156 peptides. Very few homologous proteins were matched in the proteomic database, implying that the peptides are derived from unknown proteins present in the foraminiferal organic matrices. The amino acid distribution of these peptides was queried against the uniprot database and the mollusk uniprot database for comparison. The mollusks compose a well-studied phylum that yield a large variety of biomineralization proteins. These results showed that proteins extracted from S. floresiana shells contained sequences enriched with glycine, alanine, and proline, making a set of residues that provided a signature unique to foraminifera. Three of the de novo peptides exhibited sequence similarities to peptides found in proteins such as pre-collagen-P and a group of P-type ATPases including a calcium-transporting ATPase. Surprisingly, the peptide that was most similar to the collagen-like protein was a glycine-rich peptide reported from the test and spine proteome of sea urchin. The molecules, identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry analyses, included acid-soluble N-glycoproteins with its sugar moieties represented by high-mannose-type glycans and carbohydrates. Describing the nature of the proteins, and associated molecules in the skeletal structure of living foraminifera, can elucidate the biomineralization mechanisms of these major carbonate producers in marine ecosystems. As fossil foraminifera provide important paleoenvironmental and paleoclimatic information, a better understanding of biomineralization in these organisms will have far-reaching impacts.


The risk of lymph-node metastases in patients with high-grade dysplasia or intramucosal carcinoma in Barrett's esophagus: a systematic review.
Endoscopic eradication therapy is used to treat mucosal neoplasms in Barrett's esophagus, but cannot cure cancers that have metastasized to lymph nodes. The risk of such metastases has been proposed as a reason to consider esophagectomy rather than endoscopic therapy for esophageal mucosal neoplasia. The objective of our study was to determine the frequency of lymph-node metastases in patients with high-grade dysplasia (HGD) and intramucosal carcinoma in Barrett's esophagus. We performed a systematic review using the PRISMA guidelines to identify studies that included patients who had esophagectomy for HGD or intramucosal carcinoma in Barrett's esophagus, and that reported final pathology results after examination of esophagectomy specimens. We identified 70 relevant reports that included 1,874 patients who had esophagectomy performed for HGD or intramucosal carcinoma in Barrett's esophagus. Lymph-node metastases were found in 26 patients (1.39 % , 95 % CI 0.86 – 1.92). No metastases were found in the 524 patients who had a final pathology diagnosis of HGD, whereas 26 (1.93 % , 95 % CI 1.19 – 2.66 %) of the 1,350 patients with a final pathology diagnosis of intramucosal carcinoma had positive lymph nodes. The risk of unexpected lymph-node metastases for patients with mucosal neoplasms in Barrett's esophagus is in the range of 1 – 2 %. Esophagectomy has a mortality rate that often exceeds 2 %, with substantial morbidity and no guarantee of curing metastatic disease. Therefore, the risk of lymph node metastases alone does not warrant the choice of esophagectomy over endoscopic therapy for HGD and intramucosal carcinoma in Barrett's esophagus.


Telling ecological networks apart by their structure: An environment-dependent approach.
The network architecture of an ecological community describes the structure of species interactions established in a given place and time. It has been suggested that this architecture presents unique features for each type of ecological interaction: e.g., nested and modular architectures would correspond to mutualistic and antagonistic interactions, respectively. Recently, Michalska-Smith and Allesina (2019) proposed a computational challenge to test whether it is indeed possible to differentiate ecological interactions based on network architecture. Contrary to the expectation, they found that this differentiation is practically impossible, moving the question to why it is not possible to differentiate ecological interactions based on their network architecture alone. Here, we show that this differentiation becomes possible by adding the local environmental information where the networks were sampled. We show that this can be explained by the fact that environmental conditions are a confounder of ecological interactions and network architecture. That is, the lack of association between network architecture and type of ecological interactions changes by conditioning on the local environmental conditions. Additionally, we find that environmental conditions are linked to the stability of ecological networks, but the direction of this effect depends on the type of interaction network. This suggests that the association between ecological interactions and network architectures exists, but cannot be fully understood without attention to the environmental conditions acting upon them.


The effect of ouabain, dinitrophenol, and lithium on the pacemaker current in sheep cardiac Purkinje fibers.
We studied the effect of ouabain and other inhibitors of the Na-K pump on the pacemaker current (IK2) in sheep cardiac Purkinje fibers. We found that exposure to ouabain (2 X 10(7) M) caused an apparent decrease in the amplitude of the IK2 activation curve. We also found that a similar effect was caused by exposure to dinitrophenol (DNP) or lithium-substituted Tyrode's solution. Our studies showed that after prolonged (more than 60 minutes) exposure to ouabain a characteristic current noise appeared and IK2 was replaced by an oscillatory inward current (IOS). The apparent threshold for IOS was -50 to -60 mV and the peak amplitude of this current increased with increasing levels of depolarization positive to threshold. These results suggest that (1) the apparent decrease in IK2 may be a consequence of ionic redistribution due to Na-K pump inhibition; (2) cardiac glycosides cause abnormal impulse generation by an ionic mechanism separate from IK2 and involving IOS.


Basaloid squamous cell carcinoma of the tonsil.
Basaloid squamous cell carcinoma (BSCC) is a rare and aggressive variant of squamous cell carcinoma that mainly arises in the upper aerodigestive tract. The tonsil is a rare site of BSCC development and only fourteen cases have been reported in the international literature. We report here on the case of a 56-year-old man who presented with mild dysphagia. Computed tomography and examination of the oropharynx revealed a suspicious-looking, bulky mass on the right tonsil. Histopathological examination confirmed the presence of BSCC. The patient had cervical lymph node metastases and pulmonary metastases and was treated with chemotherapy and concurrent radiation. Despite the metastases the patient is still alive 3 years after the initial diagnosis.


Onyx embolization of a carotid cavernous fistula via direct transorbital puncture.
The treatment of indirect carotid cavernous fistulas (CCFs) is challenging and primarily accomplished by endovascular means utilizing a variety of embolic agents. Transvenous access to the cavernous sinus is the preferred method of embolizaiton of indirect CCFs as they are frequently associated with numerous small-caliber meningeal branches. Although the inferior petrosal sinus is the simplest, shortest, and most commonly used venous route to the cavernous sinus, the superior ophthalmic vein, superior petrosal sinus, basilar plexus, and pterygoid plexus present other endovenous options. Occasionally, however, use of these venous routes may not be possible due to vessel tortuosity or sinus thrombosis and occlusion. The authors report a case of an indirect CCF that could not be treated endovascularly due to inability to access the cavernous sinus via a transfemoral transvenous approach. Angiography revealed a small, deeply located superior ophthalmic vein that was thought to be suboptimal for a direct cutdown. The cavernous sinus was cannulated directly via a transorbital approach using fluoroscopic guidance with a 3D skull reconstruction overlay. The fistula was subsequently obliterated using ethylene vinyl alcohol copolymer (Onyx). The technique and advantages of both 3D osseous reconstruction as well as Onyx embolization are discussed.


The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current.
The common polymorphism SCN5A-S1103Y (∼13% allelic frequency in African Americans) is a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome. Prompted by a case of autopsy-negative SUD in a 23-year-old African American man who collapsed while playing football, we hypothesized that S1103Y interacted with other SCN5A variants to pathologically modify sodium current (I(Na)). Mutational analysis of arrhythmia-associated genes in the victim revealed the variants SCN5A-R680H and SCN5A-S1103Y. These variants were made both separately and in the same cDNA construct of the alternative splice variant backgrounds (SCN5A-Q1077del and Q1077) and expressed in HEK293 cells. In the most abundant SCN5A-Q1077del, late I(Na) for S1103Y alone was not significantly different from wild type (WT). However, late I(Na) for R680H, R680H+S1103Y (coexpressed), and R680H/S1103Y (on the same cDNA) was increased 2.1-, 3.4-, and 3.6-fold, respectively, compared with WT. Intracellular acidosis (pH 6.7) increased late I(Na) for S1103Y, R680H, R680H+S1103Y, and R680H/S1103Y by 2.2-, 2.4-, 5.0-, and 5.5-fold, respectively, compared with WT at pH 6.7. Expression in the less abundant SCN5A-Q1077 showed no increased late I(Na). This is the initial report of a functional interaction for the common polymorphism S1103Y with another mutation in the major transcript Q1077del of SCN5A. The "double hit" and environmental factor of acidosis may have converged to cause arrhythmic sudden death in this case.