Alternaria tenuissima Causing Alternaria Blight on Pigeonpea in India.
Pigeonpea (Cajanus cajan (L.) Millsp.) is a major grain legume of the tropics and subtropics worldwide. In India, pigeonpea is the third most important food legume after chickpea and field pea. Blight symptoms on pigeonpea were observed in alarming proportion during the 2009 through 2011 crop seasons in Andhra Pradesh state in India. Disease incidence ranged from 20 to 80% irrespective of cultivars sown. Infected plants in the field showed symptoms on all aerial parts of the plant (leaves, stems, buds, and pods) irrespective of age of the plant and leaves. Symptoms on leaves were small, circular, necrotic spots that developed quickly forming typical concentric rings (1). Later, these spots coalesced and caused blighting of leaves. Spots were initially light brown and later turned dark brown. On stems, spots were sunken with concentric rings. In severe infection, defoliation and drying of infected leaves, branches, and flower buds was observed. The fungus was successfully isolated from all the infected plant parts (leaves, stem, buds, and pods) on potato dextrose agar (PDA) medium. After 4 to 5 days of incubation at 28 ± 1°C with a 12-h photoperiod, the fungus produced colonies that were regular and flat. The periphery of the colony was olive green with a black center. Monoconidial isolations were used to establish a pure culture of the fungus. Conidiophores were short, arising singly, and were 8.86 mm long and 2.97 mm thick. Conidia varied from 15.78 to 28.70 mm long and 8.03 to 13.47 mm wide. Very small beak (1.6 to 3.2 mm) or no beak was observed. Horizontal and vertical septations of conidia varied from four to six and two to four, respectively. The pathogenicity test was conducted on 8- to 10-day-old pigeonpea plants of cultivar ICPL 87119 by spraying with a conidial suspension (5 × 105 conidia/ml). Inoculated plants were covered with polythene bags and kept in a greenhouse at 28 ± 1°C with a 12-h photoperiod. After 48 h, the polythene bags were removed. Ten days after inoculation, symptoms were similar to those observed in fields. This experiment was conducted twice with two independent sets of plants. No symptoms were observed in water-inoculated control plants. The fungus was reisolated from the inoculated plants. On the basis of the morphological characteristics, the pathogen was tentatively identified as Alternaria tenuissima. The identification was further confirmed by the rDNA and internal transcribed spacer (ITS) primer. The ITS region of rDNA was amplified with ITS 1 and ITS 4 primers. Both orientation sequenced amplicons (481 bp) were submitted to GenBank (Accession No. JQ074094). A BLASTn search revealed 99% similarity to A. tenuissima (Accession No. HQ343444). To our knowledge, this is the first report of molecular identification of A. tenuissima causing Alternaria blight in pigeonpea in India. Reference: (1) Kannaiyan, J. and Nene, Y. L. 1977. Trop. Grain Legume Bull. 9:34.


Expiratory flow limitation during sleep in heavy snorers and obstructive sleep apnoea patients.
Inspiratory flow limitation (FL) during sleep has previously been reported both in obstructive sleep apnoea (OSA) patients and heavy snorers (HS). Recent results from this laboratory have shown the occurrence both of inspiratory and expiratory flow limitation during muscular relaxation in awake healthy subjects and OSA patients. In this study, we have investigated whether expiratory flow limitation occurs during sleep in heavy snorers and in patients with OSA. We studied four nonapnoeic, heavy snorers and five OSA patients. Airflow was measured with a pneumotachograph attached to a tight-fitting mask, and supraglottic pressure with a catheter placed at the supraglottic level. Scoring for flow limitation was achieved by visual inspection of 200 breaths recorded during sleep. About 20% of the respiratory cycles presented isolated inspiratory flow limitation. Approximately the same percentage was observed in heavy snorers and OSA patients. Isolated expiratory flow limitation was less frequently recorded. Coupled inspiratory and expiratory flow limitations were more numerous, especially in heavy snorers. We conclude that both in heavy snorers and obstructive sleep apnoea patients, inspiratory flow limitation is associated with expiratory flow limitation. This suggests that upper airway obstruction during sleep is both an inspiratory and expiratory event.


Relation between severity of Alzheimer's disease and costs of caring.
Data from the Canadian Study of Health and Aging (CSHA) were used to examine the relation between severity of Alzheimer's disease, as measured by the Mini-Mental State Examination (MMSE), and costs of caring. The CSHA was a community-based survey of the prevalence of dementia, including subtypes such as Alzheimer's disease, among elderly Canadians. Survey subjects with a diagnosis of possible or probable Alzheimer's disease were grouped into disease severity levels of mild (MMSE score 21-26), mild to moderate (MMSE score 15-20), moderate (MMSE score 10-14) and severe (MMSE score below 10). Components of care available from the CSHA were use of nursing home care, use of medications, use of community support services by caregivers and unpaid caregiver time. Costs were calculated from a societal perspective and are expressed in 1996 Canadian dollars. The annual societal cost of care per patient increased significantly with severity of Alzheimer's disease. The cost per patient was estimated to be $9451 for mild disease, $16,054 for mild to moderate disease, $25,724 for moderate disease and $36,794 for severe disease. Institutionalization was the largest component of cost, accounting for as much as 84% of the cost for people with severe disease. For subjects living in the community, unpaid caregiver time and use of community services were the greatest components of cost and increased with disease severity. The societal cost of care of Alzheimer's disease increases drastically with increasing disease severity. Institutionalization is responsible for the largest cost component.


Prostaglandin E1 increases in vivo and in vitro calcitriol biosynthesis in rabbits.
Prostaglandins have an anabolic effect on bone. Possible mediation of this effect is via calcitriol. This study determines in vivo and in vitro effects of PGE(1) on calcitriol synthesis. In vivo: rabbits received intravenous vehicle or prostaglandin E(1) (50 microg/day) for 20 days before measurements of serum total and ionic calcium, magnesium and phosphorus levels, total and bone-specific alkaline phosphatases, 25(OH)D(3), calcitriol, parathyroid hormone and calcitonin. In vitro: rabbit proximal renal tubules were incubated with 25(OH)D(3) (8 microM) together with PGE(1) (2.82 x 10(-6) M) and the prostaglandin receptor inhibitor AH6809 (10(-4) M) in selected samples. After 5 or 30 min incubation, calcitriol production was measured by radioimmunoassay and data analysed statistically. In vivo, in groups receiving PGE(1), levels of total Ca, Mg and calcitriol increased significantly and 25 dihydroxyvitamin D(3), parathyroid hormone and calcitonin remained unchanged. In vitro, PGE(1) increased calcitriol biosynthesis and the prostaglandin inhibitor AH6809 reduced calcitriol levels significantly after prolonged incubation. In vivo and in vitro results demonstrate that PGE(1) stimulates calcitriol synthesis. This study represent a major advancement in knowledge of bone metabolism.


Genetic high throughput screening in Retinitis Pigmentosa based on high resolution melting (HRM) analysis.
Retinitis Pigmentosa (RP) involves a group of genetically determined retinal diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cone cells. Most cases of RP are monogenic, with more than 80 associated genes identified so far. The high number of genes and variants involved in RP, among other factors, is making the molecular characterization of RP a real challenge for many patients. Although HRM has been used for the analysis of isolated variants or single RP genes, as far as we are concerned, this is the first study that uses HRM analysis for a high-throughput screening of several RP genes. Our main goal was to test the suitability of HRM analysis as a genetic screening technique in RP, and to compare its performance with two of the most widely used NGS platforms, Illumina and PGM-Ion Torrent technologies. RP patients (n = 96) were clinically diagnosed at the Ophthalmology Department of Donostia University Hospital, Spain. We analyzed a total of 16 RP genes that meet the following inclusion criteria: 1) size: genes with transcripts of less than 4 kb; 2) number of exons: genes with up to 22 exons; and 3) prevalence: genes reported to account for, at least, 0.4% of total RP cases worldwide. For comparison purposes, RHO gene was also sequenced with Illumina (GAII; Illumina), Ion semiconductor technologies (PGM; Life Technologies) and Sanger sequencing (ABI 3130xl platform; Applied Biosystems). Detected variants were confirmed in all cases by Sanger sequencing and tested for co-segregation in the family of affected probands. We identified a total of 65 genetic variants, 15 of which (23%) were novel, in 49 out of 96 patients. Among them, 14 (4 novel) are probable disease-causing genetic variants in 7 RP genes, affecting 15 patients. Our HRM analysis-based study, proved to be a cost-effective and rapid method that provides an accurate identification of genetic RP variants. This approach is effective for medium sized (<4 kb transcript) RP genes, which constitute over 80% of the total of known RP genes.


Contrast-independent curvilinear structure detection in biomedical images.
Many biomedical applications require detection of curvilinear structures in images and would benefit from automatic or semiautomatic segmentation to allow high-throughput measurements. Here, we propose a contrast-independent approach to identify curvilinear structures based on oriented phase congruency, i.e., the phase congruency tensor (PCT). We show that the proposed method is largely insensitive to intensity variations along the curve and provides successful detection within noisy regions. The performance of the PCT is evaluated by comparing it with state-of-the-art intensity-based approaches on both synthetic and real biological images.


The ratio of serum paraoxonase/arylesterase activity using an improved assay for arylesterase activity to discriminate PON1(R192) from PON1(Q192).
Human serum paraoxonase (PON1) exists in 2 major polymorphic forms: Q (glutamine) or R (arginine) at codon 192. The PON1(192) activity polymorphism is substrate dependent. The PON1(Q192) isoform has a higher rate of in vitro hydrolysis of diazoxon, sarin, and soman, whereas the PON1(R192) isoform has higher activity for the hydrolysis of paraoxon and chlorpyrifos oxon. Both isoforms hydrolyze phenyl acetate at approximately the same rate. The present study described and evaluated a kinetic method of arylesterase activity determination with a modified fixed incubation method that used the oxidative coupling of phenol with 4-aminoantipyrine of phenyl acetate as the substrate. Our improved method shows that arylesterase activity is lower with the PON1(R192) isoform than with the PON1(Q192) isoform. The average activities of serum of individuals of a specific PON1(Q192) genotype showed higher arylesterase and lower paraoxonase activity than the PON1(R192) genotype. The ratio of paraoxonase/arylesterase activity showed a clear separation of all three PON1(192) genotypes with no overlap between the groups (QQ: < 5.0, QR: 5.0-11.0, RR: > 11.0). PCR has suggested that the PON1(192) phenotypes correspond to the PON1(192) genotypes. Therefore, when conducting epidemiological or mechanistic studies that examine the role of PON1 in organophosphorus or lipid metabolism, this ratio is more useful and informative than a PCR-based genotype alone.


Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility.
The cannabinoid receptor 1 (CB(1)R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB(1)R that regulate these physiological functions are unknown. CB(1)R is widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB(1)R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB(1)R in afferent and efferent branches of the vagus nerve (Cnr1(flox/flox); Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1(flox/flox); Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1(flox/flox) control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB(1)R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1(flox/flox); Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB(1)R in the vagus nerve as a key component underlying normal gastrointestinal motility.


Search for the Production of a Long-Lived Neutral Particle Decaying within the ATLAS Hadronic Calorimeter in Association with a Z Boson from pp Collisions at sqrt[s]=13 TeV.
This Letter presents a search for the production of a long-lived neutral particle (Z_{d}) decaying within the ATLAS hadronic calorimeter, in association with a standard model (SM) Z boson produced via an intermediate scalar boson, where Z→ℓ^{+}ℓ^{-} (ℓ=e, μ). The data used were collected by the ATLAS detector during 2015 and 2016 pp collisions with a center-of-mass energy of sqrt[s]=13 TeV at the Large Hadron Collider and correspond to an integrated luminosity of 36.1±0.8 fb^{-1}. No significant excess of events is observed above the expected background. Limits on the production cross section of the scalar boson times its decay branching fraction into the long-lived neutral particle are derived as a function of the mass of the intermediate scalar boson, the mass of the long-lived neutral particle, and its cτ from a few centimeters to one hundred meters. In the case that the intermediate scalar boson is the SM Higgs boson, its decay branching fraction to a long-lived neutral particle with a cτ approximately between 0.1 and 7 m is excluded with a 95% confidence level up to 10% for m_{Z_{d}} between 5 and 15 GeV.


Multi-faceted analysis and prediction for the outbreak of pediatric respiratory syncytial virus.
Respiratory syncytial virus (RSV) is a significant cause of pediatric hospitalizations. This article aims to utilize multisource data and leverage the tensor methods to uncover distinct RSV geographic clusters and develop an accurate RSV prediction model for future seasons. This study utilizes 5-year RSV data from sources, including medical claims, CDC surveillance data, and Google search trends. We conduct spatiotemporal tensor analysis and prediction for pediatric RSV in the United States by designing (i) a nonnegative tensor factorization model for pediatric RSV diseases and location clustering; (ii) and a recurrent neural network tensor regression model for county-level trend prediction using the disease and location features. We identify a clustering hierarchy of pediatric diseases: Three common geographic clusters of RSV outbreaks were identified from independent sources, showing an annual RSV trend shifting across different US regions, from the South and Southeast regions to the Central and Northeast regions and then to the West and Northwest regions, while precipitation and temperature were found as correlative factors with the coefficient of determination R2≈0.5, respectively. Our regression model accurately predicted the 2022-2023 RSV season at the county level, achieving R2≈0.3 mean absolute error MAE < 0.4 and a Pearson correlation greater than 0.75, which significantly outperforms the baselines with P-values <.05. Our proposed framework provides a thorough analysis of RSV disease in the United States, which enables healthcare providers to better prepare for potential outbreaks, anticipate increased demand for services and supplies, and save more lives with timely interventions.


Biomechanical evaluation of a titanium implant surface conditioned by a hydroxide ion solution.
Two groups of titanium dental implants, identical in geometry but different in the treatment of their surfaces, were tested in an in vivo minipig model of the mandible. The surfaces that were tested were, first, sandblasted and acid-etched; and secondly, sandblasted, acid-etched, and conditioned. The removal torque was assessed at 2, 4, and 8 weeks after implantation (n=6 animals in each healing period). The interfacial stiffness was also evaluated. All dental implants were well-integrated at the time of death. Removal torque values increased significantly over the course of 8 weeks. Removal torque and interfacial stiffness were increased for conditioned surfaces after 2 weeks, but there were no significant differences between the two surfaces. The sandblasted and acid-etched implants are the standard, and conditioning of the surface showed a tendency to increase early peri-implant formation of bone.


Visual system-response functions and estimating reflectance.
The almost-illuminant-independent achromatic variable zeta [J. Opt. Soc. Am A 11, 1003 (1994)] is supplemented by two achromatic variables, both almost illuminant-independent. The results are numerically verified and obtained by means of so-called (human) visual system-response functions, defined as those linear combinations of the color-matching functions that constitute the best possible approximations to delta functions. It is argued that they and not the cone sensitivities are basic to understanding the visual system as a color-constant signal detection system. The three variables solve the color-constancy problem and define a chromatic adaptation transform for blackbody radiators of temperature T. The generalization of the results to arbitrary well-behaved illuminants is discussed.


The sky blue method as a screening test to detect misplacement of percutaneous endoscopic gastrostomy tube at exchange.
During tube exchange for percutaneous endoscopic gastrostomy (PEG), a misplaced tube can cause peritonitis and death. Thus, endoscopic or radiologic observation is required at tube exchange to make sure the tube is placed correctly. However, these procedures cost extensive time and money to perform in all patients at the time of tube exchange. Therefore, we developed the "sky blue method" as a screening test to detect misplacement of the PEG tube during tube exchange. First, sky blue solution consisting of indigocarmine diluted with saline was injected into the gastric space via the old PEG tube just before the tube exchange. Next, the tube was exchanged using a standard method. Then, we checked whether the sky blue solution could be collected through the new tube or not. Finally, we confirmed correct placement of the tube by endoscopic or radiologic observation for all patients. A total of 961 patients were enrolled. Each tube exchange took 1 to 3 minutes, and there were no adverse effects. Four patients experienced a misplaced tube, all of which were detectable with the sky blue method. Diagnostic parameters of the sky blue method were as follows: sensitivity, 94% (95%CI: 92-95%); specificity, 100% (95%CI: 40-100%); positive predictive value, 100% (95%CI: 100-100%); negative predictive value, 6% (95%CI: 2-16%). These results suggest that the number of endoscopic or radiologic observations to confirm correct replacement of the PEG tube may be reduced to one fifteenth using the sky blue method.


[Comparison on efficacy and the safety evaluation on peripheral facial paralysis treated with electroacupuncture of different waveforms].
To use electroacupuncture (EA) of different waveforms to treat peripheral facial paralysis and assess the clinical efficacies of 3 kinds of EA waveforms (continuous wave, disperse-dense wave and intermittent wave). One hundred and twenty-nine cases of Bell's palsy were randomly divided into a continuous wave group (45 cases), a disperse-dense wave group (40 cases) and an intermittent wave group (44 cases). The acupoints were Dicang (ST 4), Jiache (ST 6), Taiyang (EX-HN 5), Xiaguan (ST 7), Hegu (LI 4), etc. The House-Brackmann (H-B) scale was used in the assessment on the day of the inclusion, in the 1st, 2nd, 3rd and 4th sessions of treatment and in 1st and 3rd months of the follow-up visit after the end of treatment separately. The cured rates were 68.9% (31/45), 60.0% (24/40) and 65.9% (29/44) in the continuous wave group, the disperse-dense wave group and the intermittent wave group separately. The results of the rank sum test showed that the efficacy comparison among the groups did not present the statistically significant difference (P > 0.05). Electroacupuncture achieves the significant clinical efficacy on peripheral facial paralysis and there are no any significant differences in the efficacy among the different waveforms. It is suggested that the clinical efficacy of electroacupuncture on the disease has nothing significant correlation with the waveforms.


Strain-induced stiffening of nanocellulose-reinforced poly(vinyl alcohol) hydrogels mimicking collagenous soft tissues.
Soft tissues possess remarkable mechanical strength for their high water content, which is hard to mimic in synthetic materials. Here, we demonstrate how strain-induced stiffening in hydrogels plays a major role in mimicking the mechanical properties of collagenous soft tissues. In particular, nanocellulose reinforced polyvinyl alcohol (PVA) hydrogels of exceptionally high water content (90-93 wt%) are shown to exhibit collagen-like mechanical behavior typical for soft tissues. High water content and co-existence of both soft and rigid domains in the gel network are the main factors responsible for strain-induced stiffening. This observed effect due to the alignment of rigid components of the hydrogel is simulated through modeling and visualized through strain-induced birefringence experiments. Design parameters such as nanocellulose aspect ratio and solvent composition are also shown to be important to control the mechanical properties. In addition, owing to their transparency (90-95% at 550 nm) and hyperelastic properties (250-350% strain), the described hydrogels are promising materials for biomedical applications, especially in ophthalmology.


Abdominal aortic aneurysm repair combined with a second surgical procedure--morbidity and mortality.
Some patients who undergo repair of an abdominal aortic aneurysm require a concomitant procedure. This study compares the morbidity and mortality rates of patients who undergo combined procedures with those who undergo aneurysmorrhaphy alone. Five hundred sixty-three elective aneurysmorrhaphies were performed in the years 1971, 1976, and 1980. Three hundred thirty-five individuals underwent aneurysm repair alone (group I), while 115 underwent at least one additional vascular procedure (group II), and 113 underwent one or more nonvascular procedures (group III) concomitant with aneurysmorrhaphy. Mortality rates for the three groups were 2.6%, 3.5%, and 6.0%. Morbidity rates were 12.8%, 26.1%, and 18.5%. The differences in rates do not achieve statistical significance, but causes of death and complications varied slightly in each group. Deaths in group I were largely due to myocardial infarction, while deaths in groups II and III were largely due to complications of operation or underlying disease. Patients who required concomitant renal artery revascularizations had the greatest number of serious complications in group II. Patients with concomitant cholecystectomy appeared to have an increase in serious complications, but concomitant herniorrhaphy or lumber sympathectomy appeared to be free of any additional morbidity.


Antiepileptic drug regimens and major congenital abnormalities in the offspring.
To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in The Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose-response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose-response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.


Return to sport matters-longer-term quality of life after ACL reconstruction in people with knee difficulties.
Many individuals experience long-term quality of life (QOL) impairment following anterior cruciate ligament reconstruction (ACLR). Factors contributing to poor QOL and psychological health >5 years after ACLR remain unclear. This study aimed to describe QOL and psychological health outcomes in people with knee difficulties (pain, symptoms, or functional limitations) 5-20 years following ACLR and identify factors explaining variability in these outcomes. Participants with knee difficulties 5-20 years following ACLR completed a battery of validated patient-reported outcomes [including the Knee injury and Osteoarthritis Outcome Score (KOOS), ACL-QOL, and the Assessment of QOL (AQoL-8D) instrument]. Multivariable linear regression was used to identify factors explaining variability in outcomes. One hundred sixty-two participants aged 38 ± 9 (mean ± SD) years completed questionnaires 9 ± 4 (range 5-20) years following ACLR. Thirty-nine percent of participants returned to competitive sport, 28% returned to a lower level, and 32% did not return to sport after ACLR. Not returning to sport after ACLR was associated with worse KOOS-QOL (β = 0.29, P = 0.001 [mean ± SD (55 ± 20)], ACL-QOL [β = 0.48, P < 0.001; (57 ± 21)], and AQoL-8D [β = 0.22, P = 0.02 (0.80 ± 0.14)]) scores. Increased body mass index (56% were overweight/obese) was related to worse QOL and more depressive symptoms. Subsequent knee surgery and contralateral ACLR were also associated with poorer QOL outcomes in these individuals.


The effects of tea on psychophysiological stress responsivity and post-stress recovery: a randomised double-blind trial.
Tea has anecdotally been associated with stress relief, but this has seldom been tested scientifically. To investigate the effects of 6 weeks of black tea consumption, compared with matched placebo, on subjective, cardiovascular, cortisol and platelet responses to acute stress, in a parallel group double-blind randomised design. Seventy-five healthy nonsmoking men were withdrawn from tea, coffee and caffeinated beverages for a 4-week wash-out phase during which they drank four cups per day of a caffeinated placebo. A pretreatment laboratory test session was carried out, followed by either placebo (n = 38) or active tea treatment (n = 37) for 6 weeks, then, a final test session. Cardiovascular measures were obtained before, during and after two challenging behavioural tasks, while cortisol, platelet and subjective measures were assessed before and after tasks. The tasks induced substantial increases in blood pressure, heart rate and subjective stress ratings, but responses did not differ between tea and placebo treatments. Platelet activation (assessed using flow cytometry) was lower following tea than placebo treatment in both baseline and post-stress samples (P < 0.005). The active tea group also showed lower post-task cortisol levels compared with placebo (P = 0.032), and a relative increase in subjective relaxation during the post-task recovery period (P = 0.036). Compared with placebo, 6 weeks of tea consumption leads to lower post-stress cortisol and greater subjective relaxation, together with reduced platelet activation. Black tea may have health benefits in part by aiding stress recovery.


Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia.
The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro ( approximately 32 kDa), pro ( approximately 28 kDa) and mature ( approximately 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.


Thinking Back about a Positive Event: The Impact of Processing Style on Positive Affect.
The manner in which individuals recall an autobiographical positive life event has affective consequences. Two studies addressed the processing styles during positive memory recall in a non-clinical sample. Participants retrieved a positive memory, which was self-generated (Study 1, n = 70) or experimenter-chosen (i.e., academic achievement, Study 2, n = 159), followed by the induction of one of three processing styles (between-subjects): in Study 1, a "concrete/imagery" vs. "abstract/verbal" processing style was compared. In Study 2, a "concrete/imagery," "abstract/verbal," and "comparative/verbal" processing style were compared. The processing of a personal memory in a concrete/imagery-based way led to a larger increase in positive affect compared to abstract/verbal processing in Study 1, as well as compared to comparative/verbal thinking in Study 2. Results of Study 2 further suggest that it is making unfavorable verbal comparisons that may hinder affective benefits to positive memories (rather than general abstract/verbal processing per se). The comparative/verbal thinking style failed to lead to improvements in positive affect, and with increasing levels of depressive symptoms it had a more negative impact on change in positive affect. We found no evidence that participant's tendency to have dampening thoughts in response to positive affect in daily life contributed to the affective impact of positive memory recall. The results support the potential for current trainings in boosting positive memories and mental imagery, and underline the search for parameters that determine at times deleterious outcomes of abstract/verbal memory processing in the face of positive information.


Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry.
The Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) randomized trial compared left atrial appendage closure against warfarin in atrial fibrillation (AF) patients with CHADS₂ ≥1. Although the study met the primary efficacy end point of being noninferior to warfarin therapy for the prevention of stroke/systemic embolism/cardiovascular death, there was a significantly higher risk of complications, predominantly pericardial effusion and procedural stroke related to air embolism. Here, we report the influence of experience on the safety of percutaneous left atrial appendage closure. The study cohort for this analysis included patients in the PROTECT AF trial who underwent attempted device left atrial appendage closure (n=542 patients) and those from a subsequent nonrandomized registry of patients undergoing Watchman implantation (Continued Access Protocol [CAP] Registry; n=460 patients). The safety end point included bleeding- and procedure-related events (pericardial effusion, stroke, device embolization). There was a significant decline in the rate of procedure- or device-related safety events within 7 days of the procedure across the 2 studies, with 7.7% and 3.7% of patients, respectively, experiencing events (P=0.007), and between the first and second halves of PROTECT AF and CAP, with 10.0%, 5.5%, and 3.7% of patients, respectively, experiencing events (P=0.006). The rate of serious pericardial effusion within 7 days of implantation, which had made up >50% of the safety events in PROTECT AF, was lower in the CAP Registry (5.0% versus 2.2%, respectively; P=0.019). There was a similar experience-related improvement in procedure-related stroke (0.9% versus 0%, respectively; P=0.039). Finally, the functional impact of these safety events, as defined by significant disability or death, was statistically superior in the Watchman group compared with the warfarin group in PROTECT AF. This remained true whether significance was defined as a change in the modified Rankin score of ≥1, ≥2, or ≥3 (1.8 versus 4.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.24 to 0.82; 1.5 versus 3.7 events per 100 patient-years; relative risk, 0.41; 95% confidence interval, 0.22 to 0.82; and 1.4 versus 3.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.22 to 0.88, respectively). As with all interventional procedures, there is a significant improvement in the safety of Watchman left atrial appendage closure with increased operator experience. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00129545.


Challenges for the cataract surgeon treating people with dementia: a qualitative study exploring anesthetic choices.
In light of the growing number of people with dementia and age-related cataract, as well as changing anesthetic practices for cataract surgery, this study aimed to explore the experiences of cataract surgeons in managing patients with dementia and making anesthetic decisions. This was a qualitative study using semistructured interviews with senior cataract surgeons from two centers in England. Fourteen surgeons were interviewed, and a thematic approach informed by grounded theory was used for the analysis. Choice of anesthesia for people with dementia was a central theme arising from the data. Surgeons varied in their thresholds for using general anesthesia. Decisions about suitability for local anesthesia were limited by time constraints and generally made rapidly and based on instinct; dementia was not always apparent at the point of preassessment. Surgeons used a variety of topical, sub-Tenon's, and sharp needle blocks for people with dementia. Surgeons discussed techniques to help patients tolerate local anesthesia, such as clear communication, a primary nurse, hand-holding, and support from an anesthetist. However, within our sample, some surgeons had had negative experiences of operating on people with dementia, where an incorrect judgment had been made that they could tolerate local anesthetic cataract surgery. This study highlights the differing practices of cataract surgeons when making anesthetic choices for people with dementia and the challenges they face. In order to avoid the situation of a patient with dementia becoming distressed during awake surgery, increased time at preassessment and anesthetic support may be beneficial.


Cerebellar volume in patients with dementia.
The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis.


Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation.
The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.


Short sleep duration and large variability in sleep duration are independently associated with dietary risk factors for obesity in Danish school children.
Lack of sleep and increased consumption of energy-dense foods and sugar-sweetened beverages (SSBs) have all been suggested as factors contributing to the increased prevalence of overweight and obesity. To evaluate whether objectively measured sleep duration (average and day-to-day variability) as well as parent-reported sleep problems are independently associated with proposed dietary risk factors for overweight and obesity in 8-11-year-old children. In this cross-sectional study, data on sleep duration and day-to-day variability in sleep duration were measured in 676 Danish, apparently healthy children by an objective measure (actigraphy) for 8 nights, and the Children's Sleep Habits Questionnaire (CSHQ) was filled out by the parents. Diet was recorded using a web-based food record for 7 consecutive days. Fasting blood samples were obtained for measurements of plasma leptin and ghrelin levels. Sleep duration (h per night) was negatively associated with energy density (ED) of the diet (β = -0.32 kJ g(-1)), added sugar (β = -1.50 E%) and SSBs (β = -1.07 E%) (all P ≤ 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (β = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (β = 0.16 kJ g(-1), P = 0.04). All of these associations were independent of potential confounders (age, sex, pubertal status, height, weight, screen time, moderate-to-vigorous physical activity and parental education and ethnicity). Our study suggests that short sleep duration, high sleep duration variability and experiencing sleep problems are all associated with a poor, obesity-promoting diet in children.


Global estimates of the burden of injury and illness at work in 2012.
This article reviews the present indicators, trends, and recent solutions and strategies to tackle major global and country problems in safety and health at work. The article is based on the Yant Award Lecture of the American Industrial Hygiene Association (AIHA) at its 2013 Congress. We reviewed employment figures, mortality rates, occupational burden of disease and injuries, reported accidents, surveys on self-reported occupational illnesses and injuries, attributable fractions, national economic cost estimates of work-related injuries and ill health, and the most recent information on the problems from published papers, documents, and electronic data sources of international and regional organizations, in particular the International Labor Organization (ILO), World Health Organization (WHO), and European Union (EU), institutions, agencies, and public websites. We identified and analyzed successful solutions, programs, and strategies to reduce the work-related negative outcomes at various levels. Work-related illnesses that have a long latency period and are linked to ageing are clearly on the increase, while the number of occupational injuries has gone down in industrialized countries thanks to both better prevention and structural changes. We have estimated that globally there are 2.3 million deaths annually for reasons attributed to work. The biggest component is linked to work-related diseases, 2.0 million, and 0.3 million linked to occupational injuries. However, the division of these two factors varies depending on the level of development. In industrialized countries the share of deaths caused by occupational injuries and work-related communicable diseases is very low while non-communicable diseases are the overwhelming causes in those countries. Economic costs of work-related injury and illness vary between 1.8 and 6.0% of GDP in country estimates, the average being 4% according to the ILO. Singapore's economic costs were estimated to be equivalent to 3.2% of GDP based on a preliminary study. If economic losses would take into account involuntary early retirement then costs may be considerably higher, for example, in Finland up to 15% of GDP, while this estimate covers various disorders where work and working conditions may be just one factor of many or where work may aggravate the disease, injury, or disorders, such as traffic injuries, mental disorders, alcoholism, and genetically induced problems. Workplace health promotion, services, and safety and health management, however, may have a major preventive impact on those as well. Leadership and management at all levels, and engagement of workers are key issues in changing the workplace culture. Vision Zero is a useful concept and philosophy in gradually eliminating any harm at work. Legal and enforcement measures that themselves support companies and organizations need to be supplemented with economic justification and convincing arguments to reduce corner-cutting in risk management, and to avoid short- and long-term disabilities, premature retirement, and corporate closures due to mismanagement and poor and unsustainable work life. We consider that a new paradigm is needed where good work is not just considered a daily activity. We need to foster stable conditions and circumstances and sustainable work life where the objective is to maintain your health and work ability beyond the legal retirement age. We need safe and healthy work, for life.


Normal T lymphocytes can express two different T cell receptor beta chains: implications for the mechanism of allelic exclusion.
We have examined the extent of allelic exclusion at the T cell receptor (TCR) beta locus using monoclonal antibodies specific for V beta products. A small proportion (approximately 1%) of human peripheral blood T cells express two V beta as determined by flow cytometric analysis, isolation of representative clones, and sequencing of the corresponding V beta chains. Dual beta T cells are present in both the CD45R0+ and CD45R0- subset. These results indicate that dual beta expression is compatible with both central and peripheral selection. They also suggest that the substantial degree of TCR beta allelic exclusion is dependent only on asynchronous rearrangements at the beta locus, whereas the role of the pre-TCR is limited to signaling the presence of at least one functional beta protein.


Malignant pleural mesothelioma: Comparison of surgery-based trimodality therapy to medical therapy at two tertiary academic institutions.
Medical management based on palliative chemotherapy is currently the standard of care in malignant pleural mesothelioma (MPM). Median survival of 12-16 months has been reported with modern chemotherapy regimens with or without anti-angiogenic agents. Multimodality therapy incorporating cytoreductive surgery, systemic chemotherapy and radiotherapy has been offered for years to fit patients with early-stage disease, but its role remains debated. Our objective was to compare overall survival in patients offered multimodality therapy in a specialized clinic setting in London, UK to that of patients offered exclusively medical treatment at another academic institution in Quebec, Canada. We retrospectively compared the survival rates of 2 separate cohorts of patients treated consecutively: Cohort 1 (n = 106) received multimodality therapy including systemic chemotherapy, extended pleurectomy/decortication (P/D) and prophylactic radiotherapy in London (United Kingdom) between 2009 and 2016, while Cohort 2 (n = 98) received medical treatment at the Quebec Heart and Lung Institute (Canada) during the same period. In Cohort 1, all patients but two completed trimodality therapy. In cohort 2, 51 % received palliative care only and 40 % received systemic chemotherapy. Median survival was 32 months vs 10 months in Cohort 1 and Cohort 2, respectively (hazard ratio with age, gender, pathology and TNM staging as covariates: 3.81; 95 % CI: 2.67-5.45; p < 0.0001). Similar results were obtained in sensitivity analyses, after excluding those who received best supportive care only and in a propensity score-matched analysis. Aggressive therapy of MPM using cancer-directed surgery, systemic chemotherapy and prophylactic radiotherapy may provide a significant survival benefit in selected patients.


Hierarchical modeling of gene-environment interactions: estimating NAT2 genotype-specific dietary effects on adenomatous polyps.
Data sparseness currently limits gene-environment interaction estimation. To improve effect estimates of gene-environment interactions, we give an overview of one approach, hierarchical modeling, and propose a two-stage hierarchical model. The first stage is a logistic model for the joint effects of the genetic and environmental factors. The second stage regresses the joint effects on genotype-specific enzymatic activity of the environmentally derived substrate. The model is illustrated using a case-control study of adenomas of the large bowel, for which NAT2 genotype and dietary data were collected. The first-stage interactions of dietary components and genotype were regressed on initial conversion rates of dietary heterocyclic amines to aryl nitrenium ions. We fit the hierarchical model by penalized likelihood. Compared to effect estimates from maximum-likelihood logistic regression, hierarchical results are more reasonable and precise. These results lend further support to previous observations that hierarchical regression is preferable to ordinary logistic regression when multiple factors and their interactions are being studied. We propose that hierarchical modeling can act as a bridge between molecular epidemiology studies and laboratory data, combining both efficiently.


Paternal care in the mound-building mouse reduces inter-litter intervals.
In many rodent species males display paternal behaviour. The primary reported effect of this paternal care is to increase pup survival. In mammal females, pregnancy and lactation are energetically demanding, especially when they are concurrent in post-partum reproduction. To face this energy requirement, females generally lengthen the duration of their post-partum pregnancy. In the present study we tested whether paternal care could affect this duration in the monogamous mound building mouse Mus spicilegus. In this species, females have a short reproductive life that does not exceed 4 months. Reduction of inter-delivery latencies would then be an efficient way to increase reproductive success. In a male removal experiment, we showed that inter-delivery latency was shortened by male presence. Moreover, behavioural estimations of paternal involvement were correlated with inter-delivery latency. The longer the male spent inside the nest the shorter the inter-delivery latency. In the mound-building mouse, the female might be able to monopolise the parental care of a single male, which could be important for the evolution of monogamy. The characteristics of first reproduction as compared to post-partum reproduction suggest that it may contribute to the formation of a strong and exclusive social bond between the reproductive partners.


Gray- and white-matter anatomy of absolute pitch possessors.
Absolute pitch (AP), the ability to identify a musical pitch without a reference, has been examined behaviorally in numerous studies for more than a century, yet only a few studies have examined the neuroanatomical correlates of AP. Here, we used MRI and diffusion tensor imaging to investigate structural differences in brains of musicians with and without AP, by means of whole-brain vertex-wise cortical thickness (CT) analysis and tract-based spatial statistics (TBSS) analysis. APs displayed increased CT in a number of areas including the bilateral superior temporal gyrus (STG), the left inferior frontal gyrus, and the right supramarginal gyrus. Furthermore, we found higher fractional anisotropy in APs within the path of the inferior fronto-occipital fasciculus, the uncinate fasciculus, and the inferior longitudinal fasciculus. The findings in gray matter support previous studies indicating an increased left lateralized posterior STG in APs, yet they differ from previous findings of thinner cortex for a number of areas in APs. Finally, we found a relation between the white-matter results and the CT in the right parahippocampal gyrus. In this study, we present novel findings in AP research that may have implications for the understanding of the neuroanatomical underpinnings of AP ability.


Sugar residues on proteins.
Glycoproteins have become increasingly important in the structure and function of many different mammalian systems; for example, membrane glycoproteins and glycoprotein hormones. It is, therefore, important to understand their chemistry, which would include an understanding of both the carbohydrate and protein parts of the molecule. Since the chemical characterization of the protein moiety has been extensively examined and the techniques for its characterization are well worked out, only the carbohydrate portion of glycoproteins will be reviewed in this article. The chemical nature of the carbohydrate moiety of glycoproteins will be examined. First, the types of monosaccharides present in animal systems, especially those in the mammalian systems, will be described. Next, various types of simple and complex carbohydrate chains will be discussed to establish the diversity, size, and number of chains present in the carbohydrate units in different glycoproteins. Then, the type of linkages of the carbohydrate to the protein will be examined to determine if the primary sequence of protein is important in determining the size and type of carbohydrate chains present in glycoproteins. Finally, the current methods of structural elucidation such as monosaccharide sequence, intersugar bonds, and anomeric linkages in the carbohydrate moiety of glycoproteins will be reviewed. These methods include the techniques of periodate oxidation, methylation, partial acid hydrolysis, and specific glycosidase digestion of glycoproteins, as well as the latest techniques using micromethods of carbohydrate quantitation and characterization involving gas chromatography and mass spectrometry. The function of the carbohydrate in glycoproteins will also be considered. First, hormone glycoproteins will be discussed in their relationship to the immunological and biological function of the glycoprotein when the carbohydrate is sequentially removed. Next, the function of the carbohydrate in the turnover of glycoproteins will be discussed. These topics will be considered in order to develop an understanding of a specific function(s) of the carbohydrate in glycoproteins.


A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network.
The transcriptional activity of the p53 protein is central to its role in tumor suppression. Identification of the complete repertoire of p53-regulated genes is critical for dissecting the complexity of the p53 network. Although several different approaches have been used to characterize the p53 genetic program, we still lack a comprehensive molecular understanding of how p53 prevents cancer. Using a computational approach, we generated a genome-wide map of p53 binding sites (p53BS) to identify novel p53 target genes. We show that the presence of nearby p53BS can identify new proapoptotic members of the Bcl2 family. We show that p53 binds to p53BS identified in the BCL-G/BCL2L14 gene and that induction of this gene contributes to p53-mediated apoptosis. We found that p53 activates the COL18A1 gene encoding the precursor for the antiangiogenic factor endostatin. We also show that p53 up-regulates the MAP4K4 gene and activates the c-Jun NH2-terminal kinase (JNK) pathway to drive apoptosis. Thus, unbiased mapping of the genomic landscape of p53BS provides a systematic and complementary approach to identify novel factors and connections in the p53 genetic network. Our study illustrates how systematic genomic approaches can identify binding sites that are functionally relevant for a p53 transcriptional program. The genetic link among p53, antiangiogenic factors, and the JNK signaling pathway adds new dimensions to understanding p53 function in highly connected genetic networks.


Cellular competition modulates survival and selection of CD8+ T cells.
In this investigation we compare the repopulation of the CD8+ T cell compartments of bone marrow (BM) chimeras by either normal nontransgenic or T cell receptor (TcR) alpha beta-transgenic (TG) CD8+ T cells, the fate of TG and non-TG CD8+ T cells in different parabionts and the survival of TG and non-TG peripheral CD8+ T cells after transfer into athymic hosts. We found that cellular competition among CD8 T cells occurs at several steps of T cell differentiation including a) during the DN to DP transition, b) positive selection in the thymus, c) export from the thymus and d) in the periphery. Comparison of the results obtained in the BM chimeras and in the parabionts shows that an important step of T cell selection occurs during seeding of peripheral lymphoid tissues. Once established, peripheral T cells resist replacement by recent thymus migrants, i.e. in the periphery, selection of T cell repertoires follows the rule "first come, first served". Peripheral dominance correlates with T cell activation and division. Cell cycling and CD44 expression are more frequent among non-TG CD8 T cells than TG CD8 T cells and within the latter, more frequent among P14 TG CD8 T cells than anti-HYTG CD8 T cells. Thus, in the absence of intentional immunization, the frequencies of CD8+ T cells follow a hierarchy of selection in which non-TG > or = P14 TG > anti-HY TG. We also show that the equilibrium size and the fate of one CD8 T cell population differs according to the presence or absence of other CD8 T cell populations. Under these circumstances, selection of T cell repertoires and T cell survival and memory rely not only on the interactions of each T cell with their respective ligands, but also on the nature and number of other competing cells.


Hyperpolarized (129)Xe MRI: a viable functional lung imaging modality?
The majority of researchers investigating hyperpolarized gas MRI as a candidate functional lung imaging modality have used (3)He as their imaging agent of choice rather than (129)Xe. This preference has been predominantly due to, (3)He providing stronger signals due to higher levels of polarization and higher gyromagnetic ratio, as well as its being easily available to more researchers due to availability of polarizers (USA) or ease of gas transport (Europe). Most researchers agree, however, that hyperpolarized (129)Xe will ultimately emerge as the imaging agent of choice due to its unlimited supply in nature and its falling cost. Our recent polarizer technology delivers vast improvements in hyperpolarized (129)Xe output. Using this polarizer, we have demonstrated the unique property of xenon to measure alveolar surface area noninvasively. In this article, we describe our human protocols and their safety, and our results for the measurement of the partial pressure of pulmonary oxygen (pO(2)) by observation of (129)Xe signal decay. We note that the measurement of pO(2) by observation of (129)Xe signal decay is more complex than that for (3)He because of an additional signal loss mechanism due to interphase diffusion of (129)Xe from alveolar gas spaces to septal tissue. This results in measurements of an equivalent pO(2) that accounts for both traditional T(1) decay from pO(2) and that from interphase diffusion. We also provide an update on new technological advancements that form the foundation for an improved compact design polarizer as well as improvements that provide another order-of-magnitude scale-up in xenon polarizer output.


Mothers against dpp participates in a DDP/TGF-beta responsive serine-threonine kinase signal transduction cascade.
Mothers against dpp (Mad) is the prototype of a family of genes required for signaling by TGF-beta related ligands. In Drosophila, Mad is specifically required in cells responding to Decapentaplegic (DPP) signals. We further specify the role of Mad in DPP-mediated signaling by utilizing tkvQ199D, an activated form of the DPP type I receptor serine-threonine kinase thick veins (tkv). In the embryonic midgut, tkvQ199D mimics DPP-mediated inductive interactions. Homozygous Mad mutations block signaling by tkvQ199D. Appropriate responses to signaling by tkvQ199D are restored by expression of MAD protein in DPP-target cells. Endogenous MAD is phosphorylated in a ligand-dependent manner in Drosophila cell culture. DPP overexpression in the embryonic midgut induces MAD nuclear accumulation; after withdrawal of the overexpressed DPP signal, MAD is detected only in the cytoplasm. However, in three different tissues and developmental stages actively responding to endogenous DPP, MAD protein is detected in the cytoplasm but not in the nucleus. From these observations, we discuss possible roles for MAD in a DPP-dependent serine-threonine kinase signal transduction cascade integral to the proper interpretation of DPP signals.


Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity.
Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4-18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.


Adaptive differentiation in seedling traits in a hybrid pine species complex, Pinus densata and its parental species, on the Tibetan Plateau.
Evidence from molecular genetics demonstrates that Pinus densata is a natural homoploid hybrid originating from the parent species Pinus tabuliformis and Pinus yunnanensis, and ecological selection may have played a role in the speciation of P. densata. However, data on differentiation in adaptive traits in the species complex are scarce. In this study, we performed a common garden test on 16 seedling traits to examine the differences between P. densata and its parental species in a high altitude environment. We found that among the 16 analyzed traits, 15 were significantly different among the species. Pinus tabuliformis had much earlier bud set and a relatively higher bud set ratio but poorer seedling growth, and P. yunnanensis had opposite responses for the same traits. P. densata had the greatest fitness with higher viability and growth rates than the parents. The relatively high genetic contribution of seedling traits among populations suggested that within each species the evolutionary background is complex. The correlations between the seedling traits of a population within a species and the environmental factors indicated different impacts of the environment on species evolution. The winter temperature is among the most important climate factors that affected the fitness of the three pine species. Our investigation provides empirical evidence on adaptive differentiation among this pine species complex at seedling stages.


Priming and de-priming of neutrophil responses in vitro and in vivo.
The activation status of neutrophils can cycle from basal through primed to fully activated ("green-amber-red"), and at least in vitro, primed cells can spontaneously revert to a near basal phenotype. This broad range of neutrophil responsiveness confers extensive functional flexibility, allowing neutrophils to respond rapidly and appropriately to varied and evolving threats throughout the body. Primed and activated cells display dramatically enhanced bactericidal capacity (including augmented respiratory burst activity, degranulation and longevity), but this enhancement also confers the capacity for significant unintended tissue injury. Neutrophil priming and its consequences have been associated with adverse outcomes in a range of disease states, hence understanding the signalling processes that regulate the transition between basal and primed states (and back again) may offer new opportunities for therapeutic intervention in pathological settings. A wide array of host- and pathogen-derived molecules is able to modulate the functional status of these versatile cells. Reflecting this extensive repertoire of potential mediators, priming can be established by a range of signalling pathways (including mitogen-activated protein kinases, phosphoinositide 3-kinases, phospholipase D and calcium transients) and intracellular processes (including endocytosis, vesicle trafficking and the engagement of adhesion molecules). The signalling pathways engaged, and the exact cellular phenotype that results, vary according to the priming agent(s) to which the neutrophil is exposed and the precise environmental context. Herein we describe the signals that establish priming (in particular for enhanced respiratory burst, degranulation and prolonged lifespan) and describe the recently recognised process of de-priming, correlating in vitro observations with in vivo significance.


Long-term community change through multiple rapid transitions in a desert rodent community.
While studies increasingly document long-term change in community composition, whether long-term change occurs gradually or via rapid reorganization events remains unclear. We used Latent Dirichlet Allocation (LDA) and a change-point model to examine the long-term dynamics of a desert rodent community undergoing compositional change over a 38-yr span. Our approach detected three rapid reorganization events, where changes in the relative abundances of dominant and rare species occurred, and a separate period of increased variance in the structure of the community. These events coincided with time periods, possibly related to climate events, where the total abundance of rodents was extremely low. There are a variety of processes that could link low abundance events with a higher probability of rapid ecological transitions, including higher importance of stochastic processes (i.e., competitive interactions or priority effects) and the removal of structuring effects of competitive dominants or incumbent species. Continued study of the dynamics of community change will provide important information not only on the processes structuring communities, but will also provide guidance for forecasting how communities will undergo change in the future.


Monte Carlo simulations of single and coupled synthetic molecular motors.
We use a minimal model to study the processive motion of coupled synthetic molecular motors along a DNA track and we present data from Monte Carlo (MC) computer simulations based on this model. The model was originally proposed by Bromley et al. [HFSP J. 3, 204 (2009)] for studying the properties of a synthetic protein motor, the "Tumbleweed" (TW), and involves rigid Y-shaped motors diffusively rotating along the track while controlled by a series of periodically injected ligand pulses into the solution. The advantage of the model is that it mimics the mechanical properties of the TW motor in detail. Both the average first passage time which measures the diffusive motion of the motors, and the average dwell time on the track which measures their processivity are investigated by varying the parameters of the model. The latter includes ligand concentration and the range and strength of the binding interaction between motors and the track. In particular, it is of experimental interest to study the dependence of these dynamic time scales of the motors on the ligand concentration. Single rigid TW motors were first studied since no previous MC simulations of these motors have been performed. We first studied single motors for which we found a logarithmic decrease of the average first passage time and a logarithmic increase of the average dwell time with increasing ligand concentration. For two coupled motors, the dependence on ligand concentration is still logarithmic for the average first passage time but becomes linear for the average dwell time. This suggests a much greater stability in the processive motion of coupled motors as compared to single motors in the limit of large ligand concentration. By increasing the number of coupled motors, m, it was found that the average first passage time of the coupled motors only increases slowly with m while the average dwell time increases exponentially with m. Thus the stability of coupled motors on the track can be considerably enhanced by their cooperative motion.


A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord.
Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery, which leads to severe disabilities in motor functions or pain. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration. In the present study, we describe the cloning, functional expression in Escherichia coli cells and purification of a recombinant αL1 Fab fragment that binds to L1 with comparable activity as the function-triggering monoclonal antibody 557.B6 and induces neurite outgrowth and neuronal survival in cultured neurons, despite its monovalent function. Infusion of αL1 Fab into the lesioned spinal cord of mice enhanced functional recovery after thoracic spinal cord compression injury. αL1 Fab treatment resulted in reduced scar volume, enhanced number of tyrosine hydroxylase-positive axons and increased linear density of VGLUT1 (vesicular glutamate transporter 1) on motoneurons. Furthermore, the number and soma size of ChAT (choline acetyltransferase)-positive motoneurons and the linear density of ChAT-positive boutons on motoneurons as well as parvalbumin-positive interneurons in the lumbar spinal cord were elevated. Stimulation of endogenous L1 by application of the αL1 Fab opens new avenues for recombinant antibody technology, offering prospects for therapeutic applications after traumatic nervous system lesions.


Use of quercetin in animal feed: effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken.
Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.


Mass transport of macromolecules within an in vitro model of supragingival plaque.
The aim of this study was to examine the diffusion of macromolecules through an in vitro biofilm model of supragingival plaque. Polyspecies biofilms containing Actinomyces naeslundii, Fusobacterium nucleatum, Streptococcus oralis, Streptococcus sobrinus, Veillonella dispar, and Candida albicans were formed on sintered hydroxyapatite disks and then incubated at room temperature for defined periods with fluorescent markers with molecular weights ranging from 3,000 to 900,000. Subsequent examination by confocal laser scanning microscopy revealed that the mean square penetration depths for all tested macromolecules except immunoglobulin M increased linearly with time, diffusion coefficients being linearly proportional to the cube roots of the molecular weights of the probes (range, 10,000 to 240,000). Compared to diffusion in bulk water, diffusion in the biofilms was markedly slower. The rate of diffusion for each probe appeared to be constant and not a function of biofilm depth. Analysis of diffusion phenomena through the biofilms suggested tortuosity as the most probable explanation for retarded diffusion. Selective binding of probes to receptors present in the biofilms could not explain the observed extent of retardation of diffusion. These results are relevant to oral health, as selective attenuated diffusion of fermentable carbohydrates and acids produced within dental plaque is thought to be essential for the development of carious lesions.


Early Detection of Alzheimer's Disease with Blood Plasma Proteins Using Support Vector Machines.
The successful development of amyloid-based biomarkers and tests for Alzheimer's disease (AD) represents an important milestone in AD diagnosis. However, two major limitations remain. Amyloid-based diagnostic biomarkers and tests provide limited information about the disease process and they are unable to identify individuals with the disease before significant amyloid-beta accumulation in the brain develops. The objective in this study is to develop a method to identify potential blood-based non-amyloid biomarkers for early AD detection. The use of blood is attractive because it is accessible and relatively inexpensive. Our method is mainly based on machine learning (ML) techniques (support vector machines in particular) because of their ability to create multivariable models by learning patterns from complex data. Using novel feature selection and evaluation modalities, we identified 5 novel panels of non-amyloid proteins with the potential to serve as biomarkers of early AD. In particular, we found that the combination of A2M, ApoE, BNP, Eot3, RAGE and SGOT may be a key biomarker profile of early disease. Disease detection models based on the identified panels achieved sensitivity (SN) > 80%, specificity (SP) > 70%, and area under receiver operating curve (AUC) of at least 0.80 at prodromal stage (with higher performance at later stages) of the disease. Existing ML models performed poorly in comparison at this stage of the disease, suggesting that the underlying protein panels may not be suitable for early disease detection. Our results demonstrate the feasibility of early detection of AD using non-amyloid based biomarkers.


En Plaque Pituitary Adenoma within a Rathke's Cleft Cyst: Report of Three Cases.
Concomitant pituitary adenomas and Rathke's cleft cysts (RCCs) are rare. These coexisting lesions are difficult to diagnose preoperatively due to their variable signal intensity on magnetic resonance imaging (MRI) and position of the RCC. We describe three cases of coexisting pituitary adenoma and RCC, and review the relevant literature. In our cases, the RCCs were relatively large and the en plaque adenomas appeared as enhanced cyst walls on MRI examination. We also report the clinical, radiologic, surgical, and histopathologic findings of each case.


How are acute care nurse practitioners enacting their roles in healthcare teams? A descriptive multiple-case study.
In many countries, acute care nurse practitioners contribute to patient care through an expanded scope of practice that includes nursing and medical activities. There have been calls across nations to establish better understanding of how nurse practitioners enact their roles in healthcare teams. The 2006 introduction of cardiology nurse practitioners in Quebec, Canada provides an opportunity to examine this process more closely. The purpose of the study is to understand how nurse practitioners enact the medical and expanded nursing portions of their role in healthcare teams. A descriptive multiple-case study design was used. The study was conducted in two university-affiliated teaching hospitals in Quebec. Data were collected from March 2009 to May 2009. Data sources included interviews (N=59), field notes, documents, and a time and motion study (N=108 h 53 min) of nurse practitioner activities using a validated observation tool. The interviews were conducted individually or in groups. Content analysis was used to analyse the qualitative data. Descriptive statistics were generated for the time and motion study. The clinical role component, including nursing and medical activities, occupied the largest portion of the nurse practitioners' work time. The pace of nurse practitioner work activities was faster in the first half of the workday in response to patient care demands. The enacted nurse practitioner scope of practice was sensitive to the local context, and the needs of team members, patients and families. Nursing and medical leadership, and the transfer of prescriptive authority and decision-making autonomy affected how nurse practitioners enacted the medical and expanded nursing portions of their roles. Participants believed the pace of work influenced the nurse practitioners' ability to develop relationships with team members, and enact all the components of their role. The practitioners' scope of practice changed in response to pressures inside and outside healthcare teams or a lack of healthcare system structures. The study findings appear to be applicable to nurse practitioners working in other specialties, and in other countries. Future research needs to examine how the pace of work affects the nurse practitioners' ability to provide care.


Taekwondo training and fitness in female adolescents.
In this study, we determined the specificity of a low frequency taekwondo training programme on physical fitness levels in adolescent females who receive limited physical education instruction (i.e. 2 days per week). Major components of physical fitness assessed were: skeletal muscle fitness (hand grip strength, bent arm hang, standing long jump, and isokinetic strength), flexibility (sit-and-reach test), speed and agility (10 × 5-m shuttle run), and cardiovascular fitness (VO(2max) and 20-m shuttle run). Changes in body composition were also assessed (dual X-ray absorptiometry, DXA). Participants were divided into two groups, a taekwondo training group (n = 21), which trained 50 min a day, 2 days per week for 12 weeks, and a control group (n = 10). Taekwondo training improved isokinetic strength, standing long jump, and sit-and-reach performance. Body fat mass and percent body fat were reduced. No changes in grip strength, bent arm hang time, speed and agility, or cardiorespiratory fitness were observed. Results indicate that low frequency taekwondo training in adolescent females produces beneficial changes in skeletal muscle fitness, flexibility, and body composition in a relatively short period of time. Consequently, this specific type of training can be useful to female adolescents in structured school environments where physical education classes are limited and there is little free time for physical activity.


A pH-sensitive chloride current in the chemoreceptor cell of rat carotid body.
1. Cardiorespiratory response to acidosis is initiated by the carotid body. 2. The direct effect of extracellular pH (pH(o)) on the chloride currents of isolated chemoreceptor cells of the rat carotid body was investigated using the whole-cell patch-clamp technique. 3. On applying intra- and extracellular solutions with a symmetrical high-Cl(-) content and with the monovalent cations replaced with membrane-impermeant ones, an inwardly rectifying Cl(-) current was found. 4. The current activated slowly and did not display any time-dependent inactivation. Current activation was present at membrane potentials negative to 0 mV (pH(o) = 7.0). 5. The current was activated by extracellular acidosis and inhibited by alkalosis in the physiologically relevant pH range of 7.0-7.8. 6. The current was reduced by 0.1 mM Cd2+ to the level of the leak current and by 1 mM anthracene-9-carboxylic acid (9-AC) to about 40 %, while 0.1 mM Ba2+ had no effect. 7. Application of 1 mM 9-AC caused a slow but statistically significant increase in the resting pH(i) (from a mean of 7.29 to 7.37 in 5 min) in clusters of chemoreceptor cells in CO(2)/HCO3(-)-buffered media as measured with carboxy-SNARF-1. 8. When membrane potential changes were estimated in the cell-attached mode, 1 mM 9-AC hyperpolarized three out of five tested cells (by 14 mV in average) incubated in CO(2)/HCO3(-)-buffered media. 9. In summary, chemoreceptor cells express an inwardly rectifying Cl(-) current, which is directly regulated by pH(o). The current may participate in intracellular acidification and membrane depolarization during acidic challenge.


Ubiquitous computing in shared-care environments.
In light of future challenges, such as growing numbers of elderly, increase in chronic diseases, insufficient health care budgets and problems with staff recruitment for the health-care sector, information and communication technology (ICT) becomes a possible means to meet these challenges. Organizational changes such as the decentralization of the health-care system lead to a shift from in-hospital to both advanced and basic home health care. Advanced medical technologies provide solutions for distant home care in form of specialist consultations and home monitoring. Furthermore, the shift towards home health care will increase mobile work and the establishment of shared care teams which require ICT-based solutions that support ubiquitous information access and cooperative work. Clinical documentation and decision support systems are the main ICT-based solutions of interest in the context of ubiquitous computing for shared care environments. This paper therefore describes the prerequisites for clinical documentation and decision support at the point of care, the impact of mobility on the documentation process, and how the introduction of ICT-based solutions will influence organizations and people. Furthermore, the role of dentistry in shared-care environments is discussed and illustrated in the form of a future scenario.


Survey on conduct of anaesthetic monitoring in small animal practice in the UK.
An online survey was used to investigate current anaesthetic monitoring practices and the confidence level of personnel monitoring anaesthetics in small animal practices within the UK. Veterinary surgeons (VSs), registered veterinary nurses (RVNs) and student veterinary nurses (SVNs) working in the UK were invited to participate in an anonymous, internet-based survey. To gather data, the questions used free text, multiple choice or scales measuring respondent attitude or opinion. No questions were mandatory and data were analysed with descriptive statistics or inductive thematic analysis. 524 valid surveys were completed and included in the data analysis (VS n=136, RVN n=307, SVN n=81). The results indicated mainly RVNs perform pre-anaesthetic monitoring equipment checks, set-up the monitoring equipment and monitor anaesthesia and are more confident than VSs monitoring anaesthetics. VSs, RVNs and SVNs were all recognised to interpret and address changes in parameters monitored. Critical tasks pertaining to anaesthetic monitoring are being performed by personnel other than a VS, RVN or SVN. Respondents recognised the importance of monitoring in relation to patient outcome; however, a considerable proportion of respondents indicated that improving standards of monitoring was not a priority in their practice. Most respondents felt that standards of monitoring could be improved and that financial constraints were the major factor limiting improvement. Most respondents felt they would benefit from further training in anaesthetic monitoring. Variability exists in how anaesthetic monitoring is conducted. Workplace pressures afflicting veterinary staff can influence the conduct of anaesthetic monitoring and initiating change within a veterinary practice can be difficult.


Cam impingement of the hip: a risk factor for hip osteoarthritis.
Femoroacetabular impingement (FAI) is characterized by abnormal contact between the proximal femur and the acetabulum. Two subtypes have been described: pincer impingement, caused by an overcovered acetabulum; and cam impingement, which occurs as a result of an aspherical femoral head (cam abnormality). A strong correlation exists between cam impingement and the subsequent development of hip osteoarthritis (OA). Major cam abnormalities confer a high risk of OA. However, the association between cam abnormalities and the pathology of OA has been difficult to compare between studies, as different methods have been used to define the abnormality. Cam abnormalities are acquired during skeletal growth and could be influenced by high impact sporting activities. Preventative treatments aiming to reduce the incidence of cam abnormalities and subsequent OA could, therefore, be developed. In this Perspective, we discuss the current understanding of FAI, focusing on cam abnormalities and their association with OA.


Improving participation rates for women of color in health research: the role of group cohesion.
Adherence to physical activity and dietary interventions is a common challenge. Interventions that use group cohesion strategies show promise for increasing adherence, but have not been tested among women of color. The purpose of this study was to determine whether dimensions of group cohesion mediate the association between intervention condition and attendance within a community physical activity program for women of color. African American and Hispanic or Latina women (N = 310) completed measurements at baseline and post-intervention and participated in a social cohesion intervention to improve physical activity and dietary habits. Women were assigned to a physical activity or fruit and vegetable intervention group. Social and task cohesion was measured using the Physical Activity Group Environment Questionnaire (PAGE-Q). Attendance was recorded at each of six intervention sessions. Women were generally middle-age (M age = 46.4 years, SD = 9.1) and obese (M BMI = 34.4 kg/m2, SD = 7.7). The estimate of the mediated effect was significant for all group cohesion constructs, indicating both task constructs-attraction to the group's task (SE = 0.096, CI: -0.599 to -0.221) and group integration around the task (SE = 0.060, CI: -0.092 to -0.328)-and social constructs-attraction to the group's social aspects (SE = 0.046, CI: -0.546 to -0.366) and group integration around social aspects (SE = 0.046, CI: -0.546 to -0.366)-significantly mediated the association between group assignment and attendance. Both task and social constructs are important to improve attendance in health promotion interventions for women of color.


CYP2C9 structure-metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors.
The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.


Managing expansions in medical students' clinical placements caused by curricular transformation: perspectives from four medical schools.
Many challenges could occur that result in the need to handle an increase in the number of medical student clinical placements, such as curricular transformations or viral pandemics, such as COVID 19. Here, we describe four different institutions' approaches to addressing the impact of curricular transformation on clerkships using an implementation science lens. Specifically, we explore four different approaches to managing the 'bulge' as classes overlap in clerkships Curriculum leaders at four medical schools report on managing the bulge of core clinical placements resulting from reducing the duration of the foundational sciences curriculum and calendar shifts for the respective clerkship curriculum. These changes, which occurred between 2014 and 2018, led to more students being enrolled in core clinical rotations at the same time than occurred previously. Schools provided respective metrics used to evaluate the effectiveness of their bulge management technique. These data typically included number of students affected in each phase of their curricular transformation, performance on standardized examinations, and student and faculty feedback. Not all data were available from all schools, as some schools are still working through their 'bulge' or are affected by COVID-19. There is much to be learned about managing curricular transformations. Working on such endeavors in a learning collaborative such as the AMA Accelerating Change in Medical Education Initiative provided support and insights about how to survive, thrive and identifying lessons learned during curricular transformation.


Emotion regulation in adolescents with acne vulgaris: correlates of medication adherence, clinical dimensions and psychopathology symptoms: a cross-sectional study.
Acne vulgaris causes profound negative physical, psychological and social effects on self-image and a negative impact on the quality of life. Most research so far has been limited to adults, and little is known about the emotion regulation, medication adherence, clinical dimensions and psychopathology symptoms in young people with acne vulgaris. A cross-sectional analytical study was conducted in a center in western Turkey. Ninety-six adolescents with acne vulgaris and 100 controls participated in the study. All participants completed self-report questionnaires including the Strength and Difficulties Questionnaire (SDQ), Difficulties in emotion regulation scale (DERS) and Morisky medication adherence scale-8 (MMAS-8). Acne severity was assessed with The Global Acne Grading Score (GAGS). Acne vulgaris patients showed poorer SDQ and DERS scores reflecting the emotional regulation problems and psychopathological symptoms compared to healthy controls. The percentages of high, medium and low adherence were 6%, 36% and 58% for oral medication; and 17.39%, 56.52% and 26.09% for topical medication, respectively. There were significant correlations between all SDQ subscale scores and the scores for the impulsivity subscale and total scores of DERS. A statistically significant positive correlation was found between MMAS-8 and the choice of topical/oral medication. Likewise, GAGS were correlated with three specific SDQ domains: emotional symptoms, prosocial behavior and total scores, and with three specific DERS domains: clarity, strategy and total scores. Maladaptive emotion regulation strategies of patients with acne vulgaris may be associated with higher psychopathological symptoms and lower beliefs in treatment efficacy. It is important to include emotional regulation interventions to improve medication adherence and quality of health care in young acne patients.


Effects of dietary Lactobacillus plantarum and AHL lactonase on the control of Aeromonas hydrophila infection in tilapia.
This study addressed the effects of dietary Lactobacillus plantarum or/and N-acylated homoserine lactonase (AHL lactonase) on controlling Aeromonas hydrophila infection in juvenile hybrid tilapia (Oreochromis niloticus♀ × O. aureus ♂). Fish were fed Lb. plantarum subsp. plantarum strain JCM1149 (10(8) CFU/g feed) or/and AHL lactonase AIO6 (4 U/g) and were exposed to a chronic challenge of A. hydrophila NJ-1 (10(5) cells/mL) for 14 days. Intestinal (foregut) alkaline phosphatase (IAP) activities were evaluated 1 day post challenge to reflect the resistance of fish against A. hydrophila infection. Parallel groups of fish with the same dietary assignments while unchallenged were also included to investigate the effect of dietary Lb. plantarum or/and AIO6 supplementation on gut health of tilapia. The results showed that IAP activity was significantly lower in fish fed with diets supplemented with Lb. plantarum JCM1149 or the combination of Lb. plantarum JCM1149 and AIO6, indicating enhanced resistance against A. hydrophila. Light microscopy and transmission electron microscopy images of foregut revealed damage caused by A. hydrophila NJ-1, but dietary Lb. plantarumJCM1149 or/and AIO6 significantly alleviated the damages. Compared to the fish immersed in A. hydrophila NJ-1, dietary Lb. plantarum JCM1149 or AIO6 could maintain the microvilli length in the foregut of tilapia. However, among the unchallenged groups of fish, the microvilli length in the foregut of tilapia fed AIO6 (singly or combination) and the microvilli density of tilapia fed AIO6 (singly) were significantly lower than those of the control, though the microvilli density in the combination treatment was significantly improved. Additionally, the dietary Lb. plantarum JCM1149 could down-regulate the expression of stress-related gene in the gut after the acute phase. In conclusion, the dietary Lb. plantarum JCM1149 is recommended to control the A. hydrophila infection in tilapia.


Subacromial impingement syndrome--effectiveness of physiotherapy and manual therapy.
The subacromial impingement syndrome (SIS) includes the rotator cuff syndrome, tendonitis and bursitis of the shoulder. Treatment includes surgical and non-surgical modalities. Non-surgical treatment is used to reduce pain, to decrease the subacromial inflammation, to heal the compromised rotator cuff and to restore satisfactory function of the shoulder. To select the most appropriate non-surgical intervention and to identify gaps in scientific knowledge, we explored the effectiveness of the interventions used, concentrating on the effectiveness of physiotherapy and manual therapy. The Cochrane Library, PubMed, EMBASE, PEDro and CINAHL were searched for relevant systematic reviews and randomised clinical trials (RCTs). Two reviewers independently extracted data and assessed the methodological quality. A best-evidence synthesis was used to summarise the results. Two reviews and 10 RCTs were included. One RCT studied manual therapy as an add-on therapy to self-training. All other studies studied the effect of physiotherapy: effectiveness of exercise therapy, mobilisation as an add-on therapy to exercises, ultrasound, laser and pulsed electromagnetic field. Moderate evidence was found for the effectiveness of hyperthermia compared to exercise therapy or ultrasound in the short term. Hyperthermia and exercise therapy were more effective in comparison to controls or placebo in the short term (moderate evidence). For the effectiveness of hyperthermia, no midterm or long-term results were studied. In the midterm, exercise therapy gave the best results (moderate evidence) compared to placebo or controls. For other interventions, conflicting, limited or no evidence was found. Some physiotherapeutic treatments seem to be promising (moderate evidence) to treat SIS, but more research is needed before firm conclusions can be drawn.