Differential Bioaccumulation of Trace Elements and Rare Earth Elements in the Muscle, Kidneys, and Liver of the Invasive Indo-Pacific Lionfish (Pterois spp.) from Cuba.
The Indo-Pacific lionfish is a saltwater fish that inhabits the Red Sea waters and the Indian and Pacific oceans; it is an invasive species in the western Atlantic and was recently introduced into the local diet in the USA, Central and South America, and the Caribbean with the aim of controlling the invasion of this species. Due to its predatory nature, it tends to bioaccumulate metals and other contaminants via the marine food web and could thus constitute a suitable species for monitoring aquatic ecosystems. The presence and distribution of 23 trace elements and 16 rare earth elements (REEs) were investigated by inductively coupled plasma-mass spectrometry (ICP-MS) in the muscle, liver, and kidneys of lionfish from Cuba. Significant differences in metal concentrations were found in the different fish organs. The liver and kidneys registered the highest concentrations for most trace elements and for ΣREE, thus demonstrating that they are effective bioindicators of possible pollution on the environment in which fish live, and assuming great importance in the choice of early biomonitoring. Trace element concentrations in the muscle are instead of crucial interest for consumer safety. The limits set by EU regulations and Cuban guidelines for Cd and Pb in fish muscle were never exceeded, suggesting that lionfish from Cuba could therefore represent a good source of minerals and proteins for the local population. Graphical abstract.


Length of stay after infant heart surgery is related to cognitive outcome at age 8 years.
To test the hypothesis that postoperative length of stay (LOS) after infant heart surgery might be an easily measured surrogate marker for various events that culminate in later adverse cognitive outcome. Among 160 eligible patients with D-transposition of the great arteries undergoing reparative surgery in infancy, 155 (97%) were reevaluated at age 8 years with IQ and achievement testing. We explored whether LOS quartiles were associated with these outcomes when adjusting for perioperative and sociodemographic variables. Longer cardiac intensive care unit (CICU) LOS quartiles were associated at age 8 years with lower full-scale IQ (P=.02), lower verbal IQ (P=.02), and with tendencies toward lower performance IQ (P=.08) and math achievement (P=.08) in adjusted models. Compared with patients in the first quartile of CICU LOS, those in the fourth quartile had mean scores for full-scale IQ that were lower by 7.2 points (P=.01); verbal IQ, 7.3 points (P=.02); performance IQ, 5.8 points (P=.05); and math achievement, 6.0 points (P=.07). Analyses on hospital LOS quartile were similar. Longer postoperative LOS is associated with worse later cognitive function, even when adjusted for perioperative events, perfusion times, and sociodemographic variables. Further research is necessary to determine the mechanisms underlying this relation.


In vitro radiographic analysis of Nd:YAG-laser-irradiated dentin.
The aim of this study was to evaluate the effects of Nd:YAG laser irradiation on the dentin radiographic image. Previous studies have shown that Nd:YAG laser irradiation is capable of promoting morphological and chemical changes of the dentin surface, indicating the possibility of an alteration of its radiographic image. Dentin of 2-mm-thick mid-coronal sections from 68 extracted posterior teeth was irradiated for 30 s by a Nd:YAG laser (lambda=1,064 nm) on one half of its surface area. The other half was left as a control. The irradiation parameters were: 80 mJ/pulse, 0.8 W, 10 Hz, with a 320-mum flexible quartz optic fiber in contact mode. The 68 samples were radiographed with a 70-kV X-ray setup. The focus-film distance was established as 30 cm and there was no distance between the object and the film. The X-ray exposure time was set as 0.16 s and the radiographic film used was an F-speed dental film. The obtained radiographic images were submitted to a densitometric analysis. The images analyzed showed that there were statistically significant differences between the density of the irradiated dentin images and the non-irradiated dentin images. The image density data showed that the irradiated dentin radiographic images were 6.36% more radiopaque than the non-irradiated dentin images. The Nd:YAG laser irradiation of dentin is able to alter its radiographic image, producing more radiopaque images of the irradiated dentin.


Lung parenchyma transverse relaxation rates at 0.55 T.
To determine R2 and R 2 ' $$ {R}_2^{\prime } $$ transverse relaxation rates in healthy lung parenchyma at 0.55 T. This is important in that it informs the design and optimization of new imaging methods for 0.55T lung MRI. Experiments were performed in 3 healthy adult volunteers on a prototype whole-body 0.55T MRI, using a custom free-breathing electrocardiogram-triggered, single-slice echo-shifted multi-echo spin echo (ES-MCSE) pulse sequence with respiratory navigation. Transverse relaxation rates R2 and R 2 ' $$ {R}_2^{\prime } $$ and off-resonance ∆f were jointly estimated using nonlinear least-squares estimation. These measurements were compared against R2 estimates from T2 -prepared balanced SSFP (T2 -Prep bSSFP) and R 2 * $$ {R}_2^{\ast } $$ estimates from multi-echo gradient echo, which are used widely but prone to error due to different subvoxel weighting. The mean R2 and R 2 ' $$ {R}_2^{\prime } $$ values of lung parenchyma obtained from ES-MCSE were 17.3 ± 0.7 Hz and 127.5 ± 16.4 Hz (T2 = 61.6 ± 1.7 ms; T 2 ' $$ {\mathrm{T}}_2^{\prime } $$ = 9.5 ms ± 1.6 ms), respectively. The off-resonance estimates ranged from -60 to 30 Hz. The R2 from T2 -Prep bSSFP was 15.7 ± 1.7 Hz (T2 = 68.6 ± 8.6 ms) and R 2 * $$ {R}_2^{\ast } $$ from multi-echo gradient echo was 131.2 ± 30.4 Hz ( T 2 * $$ {\mathrm{T}}_2^{\ast } $$ = 8.0 ± 2.5 ms). Paired t-test indicated that there is a significant difference between the proposed and reference methods (p < 0.05). The mean R2 estimate from T2 -Prep bSSFP was slightly smaller than that from ES-MCSE, whereas the mean R 2 ' $$ {R}_2^{\prime } $$ and R 2 * $$ {R}_2^{\ast } $$ estimates from ES-MCSE and multi-echo gradient echo were similar to each other across all subjects. Joint estimation of transverse relaxation rates and off-resonance is feasible at 0.55 T with a free-breathing electrocardiogram-gated and navigator-gated ES-MCSE sequence. At 0.55 T, the mean R2 of 17.3 Hz is similar to the reported mean R2 of 16.7 Hz at 1.5 T, but the mean R 2 ' $$ {R}_2^{\prime } $$ of 127.5 Hz is about 5-10 times smaller than that reported at 1.5 T.


Hamatometacarpal fracture-dislocation: classification and treatment.
Seventeen male patients with a fourth metacarpal fracture and fifth carpometacarpal joint injury were treated. Distinct patterns of injury were recognized and in each case fell into one of three categories. Type IA lesions were characterized by subluxation or dislocation of the fifth carpometacarpal joint without hamate avulsion fracture. Type IB lesions were identical to type IA lesions except for the appearance of a small dorsal rim hamate avulsion fracture. Type II lesions were distinguished by subluxation or dislocation of the fifth carpometacarpal joint and comminution of the dorsal hamate rim. Finally, type III lesions exhibited coronal splitting of the hamate.


MiR-210-5p promotes the differentiation of human induced pluripotent stem cells into dopaminergic neural precursors by targeting SMAD4 and SUFU and treats parkinsonian rats.
The differentiation of human induced pluripotent stem cells (hiPSCs) into functional dopaminergic neural precursors is the basis of cell therapy for Parkinson's disease (PD). However, the use of small molecule inhibitors/activators in the differentiation of hiPSCs in vitro leads to cell death and low differentiation efficiency. Moreover, the mechanism of differentiation remains unclear. MiR-210-5p was increased during hiPSCs differentiation. Whether it promotes hiPSCs differentiation and transplantation needs further study. Here, we overexpressed miR-210-5p in hiPSCs to study its roles and mechanisms. We found that miR-210-5p promoted the differentiation of hiPSCs into dopaminergic neural precursors and reduced the expression of SMAD4 and SUFU meanwhile. Luciferase assays showed that miR-210-5p binded to SMAD4 and SUFU, which are key molecules in the key signals (TGF-β and SHH) of hiPSCs differentiation. Furthermore, in the effect evaluation of cell transplantation into parkinsonian rats, the degree of behavioral recovery and the growth of transplanted cells in the group overexpressed miR-210-5p were similar to those in the positive group with all small molecule inhibitors/activators. Therefore, we conclude that miR-210-5p promotes the differentiation of hiPSCs into dopaminergic neural precursors by targeting SMAD4 and SUFU. In the therapeutic evaluation of cell transplantation, miR-210-5p can replace the use of corresponding small molecule inhibitors/activators to reduce cell death. This study provides an experimental basis and a new target for the miRNA-modified differentiation of hiPSCs and cell transplantation in clinical treatment of PD in the future.


Fingertip forces and completion time for index finger and thumb touchscreen gestures.
Users actuate touchscreen computers by applying forces with their fingers to the touchscreen, although the amount and direction of the force is unknown. Our aim was to characterize the magnitude, direction and impulse of the force applied during single finger (tapping and sliding in four directions) and two finger gestures (stretch and pinch). Thirteen subjects performed repeated trials of each gesture. Mean(±SD) resultant force was 0.50(0.09)N for tap, 0.79(0.32)N to 1.18(0.47)N for sliding gestures, 1.47(0.63)N for pinch and 2.05(1.13)N for stretch. Mean resultant force was significantly less (p<0.04) for tap than for all gestures except slide right. The direction of force application was more vertical for the two-finger gestures as compared to the single- finger gestures. Tap was the fastest gesture to complete at 133(83)ms, followed by slide right at 421(181)ms. On average, participants took the longest to complete the stretch gesture at 920(398)ms. Overall, there are differences in forces, force direction, and completion times among touchscreen gestures that could be used to estimate musculoskeletal exposure and help forge guidelines to reduce risk of musculoskeletal injury.


Challenges Experienced by Rural Informal Caregivers of Older Adults in the United States: A Scoping Review.
The purpose of this scoping review was to document the state of the literature regarding the challenges experienced by rural informal caregivers of older adults in the United States. We reviewed peer-reviewed academic articles published through December 1, 2021, based on Arksey and O'Malley's framework. The initial search resulted in 1,255 articles, of which 12 studies were included for the final review. Thematic content analysis was utilized to identify emerging themes of challenges experienced by rural informal caregivers of older adults. The identified challenges include a lack of knowledge regarding resources, financial difficulties, health-related challenges, and barriers related to geographic distance. The implications of these challenges are used to shape recommendations for social work, service planning, and policy changes that can improve caregiving experiences for rural families.


Synthesis and characterization of thiolate-Ag(I) complexes by solid-state and solution NMR and their antimicrobial activity.
Silver(I) complexes of several thiolates have been prepared. These complexes have been characterized by elemental analysis and 13C NMR spectroscopy. All the Ag(I)-thiolate complexes are polymeric in nature. Therefore, 13C CP MAS NMR is being used extensively to analyze the binding site of the ligand and the nature of complexation. A significant shift difference was observed for S binding site whereas smaller shift was observed for carboxylate binding site. The antimicrobial activities for Ag(I)-glutathione complex was measured and compared with Ag(I)-captopril complex.


Improving prediction of COVID-19 mortality using machine learning in the Spanish SEMI-COVID-19 registry.
COVID-19 is responsible for high mortality, but robust machine learning-based predictors of mortality are lacking. To generate a model for predicting mortality in patients hospitalized with COVID-19 using Gradient Boosting Decision Trees (GBDT). The Spanish SEMI-COVID-19 registry includes 24,514 pseudo-anonymized cases of patients hospitalized with COVID-19 from 1 February 2020 to 5 December 2021. This registry was used as a GBDT machine learning model, employing the CatBoost and BorutaShap classifier to select the most relevant indicators and generate a mortality prediction model by risk level, ranging from 0 to 1. The model was validated by separating patients according to admission date, using the period 1 February to 31 December 2020 (first and second waves, pre-vaccination period) for training, and 1 January to 30 November 2021 (vaccination period) for the test group. An ensemble of ten models with different random seeds was constructed, separating 80% of the patients for training and 20% from the end of the training period for cross-validation. The area under the receiver operating characteristics curve (AUC) was used as a performance metric. Clinical and laboratory data from 23,983 patients were analyzed. CatBoost mortality prediction models achieved an AUC performance of 84.76 (standard deviation 0.45) for patients in the test group (potentially vaccinated patients not included in model training) using 16 features. The performance of the 16-parameter GBDT model for predicting COVID-19 hospital mortality, although requiring a relatively large number of predictors, shows a high predictive capacity.


Farmers' willingness to pay for alternative resource management practices in the Bale Eco-Region, Ethiopia: An application of choice experiment.
The purpose of this study is to investigate the preferences of people in the Bale Eco-Region (BER) for better ecosystem services and to calculate their mean Willingness to Pay (WTP) for selected attributes of conservation practices to maintain watershed's ecosystem functions, using a choice modeling approach. Results from reforestation attributes revealed that the average WTP for reforestation characteristics were 3,053 ($145.38), 2,516 ($119.83), and 1,827 ($87) Ethiopian Birr (ETB)/year for higher, medium, and low impact improvement scenarios respectively, to midland communities. Lowland respondents' mean WTP for exclosure attributes were estimated at 882 ($42), 1,558 ($74.19), and 2,383 ($113) ETB yearly for low, medium, and high impact improvement scenarios respectively. This indicates that respondents from both lowland and midland communities are willing to spend a substantial amount of resource and time (measured in terms of money) on to improve ES in the BER. The study provides valuable input to carry out a cost-benefit analysis of possible interventions conserving natural resources in the BER. Moreover, using this study was an important step for initiating the process of Payment for Ecosystem Services in the BER where local communities, in Ethiopia and beyond could contribute to rehabilitating Ecosystem Services.


The genus Megastylus Schidte (Hymenoptera, Ichneumonidae, Orthocentrinae) in China with a key to the species of China and Oriental Region.
Three new species of Megastylus Schidte, 1838 (Ichneumonidae, Orthocentrinae), M. (Dicolus) mentouense Sheng Li, sp. nov. collected from Mentougou, Beijing, M. (D.) flavicornis Sheng Li, sp. nov. from Shennongjia National Natural Reserve, Hubei and M. (Megastylus) yindianense Sheng Li, sp. nov. from Minquan, Henan, are described and illustrated. A taxonomic key to the species of Megastylus known from China and the Oriental Region is provided.


Does changing the plane of abduction influence shoulder muscle recruitment patterns in healthy individuals?
Observational laboratory study. Abduction is a movement commonly used in the assessment of shoulder dysfunction and prescription of exercises to improve shoulder function. Abduction in the scapular and coronal planes are used interchangeably. It is not known if the activation of individual shoulder muscles differ between abduction performed in these planes and therefore, if they represent different tests/exercises. To quantify and compare the muscle activation patterns and levels for each shoulder muscle during abduction performed in the scapular plane with that performed in the coronal (scapular -30°) and scapular +30° planes. Electromyographic recordings were taken from eight shoulder muscles of fourteen healthy volunteers during shoulder abduction in the scapular and coronal planes and in a plane 30° anterior to the scapular plane (scapular +30°) at 50% of maximum load. Similar average muscle activation levels were demonstrated during abduction in the scapular plane and within a 30° arc of this plane for all muscles except: middle deltoid (5% MVC higher activation in the coronal and 4% MVC lower activation in the scapular +30° plane) and upper trapezius (6% MVC lower activation in the scapular +30° plane). Activation patterns between planes for all muscles were similar (ICC(3,1) ≥ 0.87). Abduction can be performed within a 30° arc of the scapular plane with no change in shoulder muscle activation patterns. Only middle deltoid activation levels change between the scapular and coronal planes and middle deltoid and upper trapezius between the scapular and scapular +30° planes.


ATAD2 predicts poor outcomes in patients with ovarian cancer and is a marker of proliferation.
The oncogene ATPase family AAA domain‑containing protein 2 (ATAD2) has been demonstrated to promote malignancy in a number of different types of tumor; however, its expression and role in ovarian cancer (OC) remain unknown. In the present study, it was demonstrated that ATAD2 acts as both a marker and a driver of cell proliferation in OC. Immunohistochemistry (IHC) and bioinformatics analyses were used to evaluate ATAD2 expression in OC, and multi‑omics integrated analyses were used to dissect which factor resulted in its upregulation. Multiplex IHC assay was used to reveal the specific expression of ATAD2 in proliferating OC cells. CRISPR‑Cas9‑mediated gene editing was performed to investigate the effect of ATAD2 deletion on OC proliferation. The results demonstrated that ATAD2 is elevated in primary OC tissues compared with the adjacent normal tissue and metastases from the stomach. Genetic copy number amplification is a primary cause resulting in upregulation of ATAD2, and this was most frequently observed in OC. High ATAD2 expression was associated with advanced progression and predicted an unfavorable prognosis. ATAD2 could be used to identify cases of OC with a high proliferation signature and could label proliferating cells in OC. CRISPR‑Cas9‑mediated ATAD2 deletion resulted in a significant decrease in both cell proliferation and colony formation ability. Mechanistically, ATAD2‑knockdown resulted in deactivation of the mitogen‑activated protein kinase (MAPK) pathways, particularly the JNK‑MAPK pathway, resulting in suppression of proliferation. Collectively, the data from the present study demonstrated that the ATD2 gene was frequently amplified and protein expression levels were upregulated in OC. Therefore, ATAD2 may serve as an attractive diagnostic and prognostic OC marker, which may be used to identify patients with primary OC, whom are most likely to benefit from ATAD2 gene‑targeted proliferation intervention therapies.


Indomethacin in canine acute hemorrhagic pancreatitis.
The effects of indomethacin administration on hemodynamics were investigated in canine acute hemorrhagic pancreatitis (AHP). Thirteen mongrel dogs were randomly divided into a fluid treatment group, an indomethacin prophylaxis group (IMP), and an indomethacin therapy (IM) group. Indomethacin (5 mg/kg) was administered as a bolus dosage 30 min before the induction of AHP in the IMP group. In the IM group, indomethacin was also given as a bolus (5 mg/kg) in 5 min starting 30 min after the induction of AHP. AHP was induced with a mixture of trypsin and sodium taurocholate infused into the pancreatic duct. Hemodynamics were monitored during the 4.5 h of surveillance time. Heart rate did not change significantly between the groups. Indomethacin prophylaxis maintained mean arterial pressure at a significantly higher level (P less than 0.05) and prevented the initial fall in blood pressure when compared to the fluid treatment or IM group. Indomethacin increased cardiac output (P less than 0.05) in the IM group, but did not differ significantly in the IMP group in comparison with the fluid treatment group. In conclusion, the inhibition of the initial fall in blood pressure by indomethacin in AHP suggests prostaglandins to play a role in hemodynamic changes and pancreatic shock to be "septic" as evaluated by hemodynamic changes.


Protective activity of gallic acid against glyoxal -induced renal fibrosis in experimental rats.
This study was designed to evaluate the protective activity of gallic acid (GA) against glyoxal (GO) an advanced glycation intermediate-induced renal fibrosis in experimental rats. Glyoxal (i.p) at a dose of 15 mg/Kg body weight/day for 4 weeks induces renal fibrosis. GA was administered orally (100 mg/Kg body weight/day) along with GO for 4 weeks. The anti-fibrotic activity of GA was analyzed by measuring the collagen synthesis and deposition in renal tissues using mRNA expression analysis and Masson trichrome staining (MTS), respectively. The nephroprotective potential of GA was assessed by quantifying the markers of kidney damage such as serum blood-urea-nitrogen (BUN), creatinine (CR) and alkaline phosphatase (AP). Moreover, basement membrane damage in renal tissues was analysed by periodic acid Schiff's (PAS) staining. GA co-treatment markedly suppressed the GO-induced elevation in mRNA expression of collagenIand III, MMP-2, MMP-9 and NOX (p < 0.05, respectively) genes as compared with GO alone infused rats. In addition, GA co-treatment significantly attenuated the GO -induced elevation in serum markers such as BUN, CR and AP levels (p < 0.05, respectively). Furthermore, GA co-treatment restored back the decreased renal super oxide dismutase (SOD) activity (p < 0.05) thereby assuage the reactive oxygen species (ROS) generation, and maintained the normal architecture of glomerulus. The present study clearly indicates that GO -induces renal fibrosis by enhancing GO/receptor of advanced glycation end product (RAGE) induced ROS generation and GA effectively counteracted GO-induced renal fibrosis by its ROS quenching and anti-glycation activity.


Biphasic effect of danazol on human vascular endothelial cell permeability and f-actin cytoskeleton dynamics.
Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function in vitro. Primary human endothelial cells exposed to 0.01-50 μM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5 min) and lasted for over 24h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage.


Practice placement supervision: the role of the personal tutor.
Confusion regarding the role of the nurse teacher in clinical practice has resulted in a service being offered to students that varies in type, quantity and quality as perceived by students, teachers and placement staff alike: The role of the personal tutor is concerned with helping the students to develop both professionally and academically. To facilitate this, a good interpersonal relationship between student and personal tutor is essential. As interpersonal relationships take time to develop, the author advocates capitalizing on the relationship that (usually) already exists between personal tutors and students, and extending this into practice placement areas. The aim of this piece of research was to ascertain the value, as perceived by the students, of having the personal tutor supervise them in college as well as in the four branch placements of foundation studies. The methodology employed was a descriptive study utilizing a self-administered questionnaire. The population was the students in foundation studies of the Lothian College of Health Studies, and the sample was one of convenience, i.e. one cohort of students. The findings demonstrated that 55 students (n = 94) perceived value in having one nurse teacher supervising them in college and in placements compared with 39 students who did not perceive any value. The students were asked about their practice placement supervision by nurse teachers in terms of type, quantity and quality of teaching. The students in the former group rated their practice placement supervision much lower than students in the latter group.


Tuning the softness of poly(2-hydroxyethyl methacrylate) nanocomposite hydrogels through the addition of PEG coated nanoparticles.
In nanocomposites, several factors govern the enhancement of properties when a nanofiller is added into a polymer matrix. Previously, our group have demonstrated that stabilizing nanoparticles improves the dispersion of nanoparticles in a hydrogel, but their effect on viscoelastic properties remain unclear. We hypothesized that coating the nanoparticles will block matrix-nanoparticle interactions, which would then affect the transfer of stress when the hydrogel is subjected to stress. To this end, we investigated the effects that nanofillers coated with polyethylene glycol (PEG) of variable molar mass have on the properties of physical hydrogels made from poly(2-hydroxyethyl methacrylate). PEG with molar masses of 6, 20, and 35 kDa were used at different concentrations and the viscoelastic properties of the resulting hydrogels were studied and compared with control hydrogels with and without nanofillers. The coated nanofiller resulted in enhanced dispersion stabilization as the molar mass and concentration of the PEG increased. However, there were noticeable changes in viscoelastic properties. In general, the nanocomposite hydrogels exhibited reduced shear modulus, greater creep, and more accentuated shear thinning behaviour. These effects were attributed to hindered matrix-nanoparticle interactions because of the PEG coating, an increased slippage of the PHEMA chains as well as a plasticizing effect.


[Mathematical foundation for biophysical methods in fetal monitoring. I. Fetal electrocardiography].
The authors discuss the foundations of mathematical analysis of fetal electrocardiograms, with particular reference to the obtaining of ECG signal by indirect method, and signal processing.


Interest in reducing methamphetamine and opioid use among syringe services program participants in Washington State.
Methamphetamine use is increasing, and opioid use remains elevated in the US. Understanding interest in reducing/stopping substance use among people who inject drugs (PWID), as well as types of help wanted, can inform interventions. Data from the 2019 Washington State Syringe Exchange Survey were used in logistic regression analyses to assess if demographics, substance use, and concern about anxiety or depression were associated with interest in reducing/stopping substance use among people whose main drug was methamphetamine or opioids. Types of help wanted to reduce/stop use are reported. Of 583 participants included, 76 % reported opioids were their main drug, of whom 82 % were interested in reducing/stopping their opioid use. 24 % reported methamphetamine as their main drug, of whom 46 % were interested in reducing/stopping their methamphetamine use. Among those whose main drug was an opioid, female gender (AOR:2.19, p = .023) and concern about depression (AOR:3.04, p = .002) were associated with interest in reducing/stopping opioid use. Among participants whose main drug was methamphetamine, being in jail in the past year and having an infection likely related to injection (e.g., abscess) in the past year were associated with over twice the odds of interest in reducing/stopping methamphetamine use (AOR:2.14, p = .056 and 2.43, p = .052, respectively); however, these findings were not significant. Several types of help to reduce/stop use were endorsed. There were high, though differing, levels of interest in reducing/stopping opioid or methamphetamine use and in a range of support services. PWID should be asked about interest in reducing/stopping use and provided appropriate support.


Correction to: Are Clerks Proficient in the Basic Sciences? Assessment of Third-Year Medical Students' Basic Science Knowledge Prior to and at the Completion of Core Clerkship Rotations.
[This corrects the article DOI: 10.1007/s40670-021-01249-3.].


Metal levels in fodder, milk, dairy products, and tissues sampled in ovine farms of Southern Italy.
We measured Cd, Cr, Hg, Mn, and Pb levels in samples of fodder, milk, dairy products, and tissues collected from 12 ovine farms in the regions of Campania and Calabria (Southern Italy). The areas in which the farms are located show different levels of anthropogenic pressure. The main purpose of this study is the identification and the analysis of relationships among metal concentrations observed in samples representative of different links in the food chain. Particularly, we apply univariate, bivariate, and multivariate statistical techniques to identify the correlation structure of our data set and to evaluate the influence of anthropogenic activity. We discuss the results, focusing the analysis on the spatial and the temporal patterns of metal concentrations.


Anal canal and sphincter function in children with Hirschsprung disease after definitive surgery.
Anorectal manometry may be useful to objectively evaluate anorectal function following definitive pullthrough for Hirschsprung Disease (HD) but there is little published data. Our study aims to investigate anorectal manometry findings and their association with bowel function. This was a prospective observational study. Convenience sampling method was used to recruit all HD patients who had definitive pullthrough from January 2019 to December2020 in our institution. High-resolution anorectal manometry (HRAM) was used to record anal resting pressure (ARP), length of high-pressure zone (HPZ), and presence/absence of recto-anal inhibitory reflex (RAIR). The Paediatric Incontinence/Constipation Scoring System (PICSS) was scored for all participants. PICSS is a validated questionnaire with scores mapped to an age-specific normogram to denote constipation, incontinence, and their combinations. Non-parametric and chi-square tests at significance p<0.05 were conducted to examine the relationship between PICSS categories and manometry findings. Ethical approval was obtained. There were 32 participants (30 boys). Median age at participation was 26.5 months (range: 13.8-156). Twenty-four (75%) had transanal pullthrough, 8(25%) underwent Duhamel procedure. PICSS scored 10(31.3%) as normal, 8(25%) as constipation, 10(31.3%) as incontinent, and 4(12.5%) as mixed. RAIR was present in 12 patients (37.5%). HPZ, maximum ARP, mean ARP were comparable across all PICSS groups without statistically significant differences. Presence of RAIR was not significantly associated with any PICSS groups (p = 0.13). Bowel function does not appear to be significantly associated with HRAM findings after definitive pullthrough for HD, but our study is limited by small sample size. RAIR was present in 37.5% patients after pullthrough. Level II.


Reduced sleep spindle activity point to a TRN-MD thalamus-PFC circuit dysfunction in schizophrenia.
Sleep disturbances have been reliably reported in patients with schizophrenia, thus suggesting that abnormal sleep may represent a core feature of this disorder. Traditional electroencephalographic studies investigating sleep architecture have found reduced deep non-rapid eye movement (NREM) sleep, or slow wave sleep (SWS), and increased REM density. However, these findings have been inconsistently observed, and have not survived meta-analysis. By contrast, several recent EEG studies exploring brain activity during sleep have established marked deficits in sleep spindles in schizophrenia, including first-episode and early-onset patients, compared to both healthy and psychiatric comparison subjects. Spindles are waxing and waning, 12-16Hz NREM sleep oscillations that are generated within the thalamus by the thalamic reticular nucleus (TRN), and are then synchronized and sustained in the cortex. While the functional role of sleep spindles still needs to be fully established, increasing evidence has shown that sleep spindles are implicated in learning and memory, including sleep dependent memory consolidation, and spindle parameters have been associated to general cognitive ability and IQ. In this article we will review the EEG studies demonstrating sleep spindle deficits in patients with schizophrenia, and show that spindle deficits can predict their reduced cognitive performance. We will then present data indicating that spindle impairments point to a TRN-MD thalamus-prefrontal cortex circuit deficit, and discuss about the possible molecular mechanisms underlying thalamo-cortical sleep spindle abnormalities in schizophrenia.


Inhibition of virus-induced hemolysis with monoclonal antibodies to different antigenic areas on the hemagglutinin molecule of A/seal/Massachusetts/1/80 (H7N7) influenza virus.
A/seal/Massachusetts/1/80 (H7N7) influenza virus caused maximal hemolysis at pH 5.9 Monoclonal antibodies to each of the four nonoverlapping antigenic areas on the hemagglutinin molecule of the virus inhibited the hemolysis whereas those belonging to two of the groups did not inhibit hemagglutination of the virus. Hemolysis also occurred when the virus was incubated at pH 5.9 prior to addition of erythrocytes. Such hemolysis caused by acid-treated virus was inhibited with the antibodies as well. At pH 5.9, hemagglutination of neither intact virus nor hemagglutinin rosettes was inhibited with any of the monoclonal antibodies, indicating conformational change in the hemagglutinin molecule, at this pH. On the other hand, hemagglutination-inhibition was observed when the antigens were incubated with the monoclonal antibodies at pH 7.0 and then the pH was later shifted to 5.9, suggesting that antibody-binding interferes with the conformational change in the hemagglutinin molecule at pH 5.9. The present findings indicate that antibodies to the hemagglutinin of influenza virus can inhibit virus-induced hemolysis by blocking conformational change in the hemagglutinin molecule and blocking later step of fusion than the conformational change, in addition to blocking attachment of virus to the receptor of erythrocytes.


An activation domain within the walleye dermal sarcoma virus retroviral cyclin protein is essential for inhibition of the viral promoter.
Walleye dermal sarcoma virus (WDSV) is a complex retrovirus associated with seasonal dermal sarcomas. Developing tumors have low levels of accessory gene transcripts, A1 and B, and regressing tumors have high levels of full-length and spliced transcripts. Transcript A1 encodes a retroviral cyclin (rv-cyclin) with limited homology to host cyclins. The rv-cyclin is physically linked to components of the transcriptional co-activator complex, Mediator, and regulates transcription. In walleye fibroblasts, it inhibits the WDSV promoter independently of cis-acting DNA sequences. The rv-cyclin activates transcription from GAL4 promoters when fused to the GAL4 DNA binding domain. A 30 a.a. activation domain in the carboxy region can be inactivated by single point mutations, and these mutations diminish the ability of the rv-cyclin to inhibit the WDSV promoter. When fused to glutathione S-transferase, the rv-cyclin, its carboxy region, and the activation domain pull down components of transcription complexes from nuclear extracts, and pull down is lost by mutation of the activation domain.


Phantom-based assessment of motion and needle targeting accuracy of robotic devices for magnetic resonance imaging-guided needle biopsy.
The current study proposes simple methods for assessing the performance of robotic devices intended for Magnetic Resonance Imaging (MRI)-guided needle biopsy. In-house made agar-based breast phantoms containing biopsy targets served as the main tool in the evaluation process of an MRI compatible positioning device comprising a needle navigator. The motion accuracy of mechanical stages was assessed by calliper measurements. Laboratory evaluation of needle targeting included a repeatability phantom test and a laser-based method. The accuracy and repeatability of needle targeting was also assessed by MRI. The maximum error of linear motion for steps up to 10 mm was 0.1 mm. Needle navigation relative to the phantom and alignment with the various biopsy targets were performed successfully in both the laboratory and MRI settings. The proposed biopsy phantoms offered tissue-like signal in MRI and good haptic feedback during needle insertion. The proposed methods could be valuable in the process of validating the accuracy of MRI-guided biopsy robotic devices in both laboratory and real environments.


Effects of Therapeutic Ultrasound on Growth Plates: A Systematic Review.
The aim of this systematic review was to evaluate studies reporting on the effects of therapeutic ultrasound on the physis. Eight studies were included in the final analysis, all of which were animal studies. At higher doses, studies found skin and bone necrosis and inhibition of growth, while in lower doses some studies found that ultrasound had a transient stimulatory effect on growth, increased thickness of the hypertrophic zone, and increased thickness of the whole growth plate. Overall, experimental evidence in animal models suggests that therapeutic ultrasound, even at low doses, might induce microscopic changes to the histology of the growth plate. While we found no reports of growth disturbance in humans, given the histological changes found in animal studies, the current limited literature seems to support the recommendation that the application of therapeutic ultrasound around the physis should be avoided.


Fluorescence analysis of the size of a binding pocket of a peptide receptor at natural abundance.
We have studied the topography of interaction of a family of fluorescent formyl peptides containing four (CHO-Met-Leu-Phe-Lys-fluorescein), five (CHO-Met-Leu-Phe-Phe-Lys- fluorescein), and six (CHO-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein and CHO-Met-Leu-Phe-Phe-Phe-Lys- fluorescein) amino acids with their receptor using spectroscopic methods adapted to small sample volumes. Only the fluorescent peptides containing four and five amino acids were quenched upon binding to the receptor, indicating physical contact of the chromophore with the receptor. In contrast, only the hexapeptides were accessible to antibodies to fluorescein. Taken together, these results suggest that the carboxy terminus of the tetrapeptide or the pentapeptide is protected in the receptor binding pocket while the fluorescein on the carboxy terminus of either hexapeptide is exposed and recognized by the antibody to fluorescein. These results indicate that the binding pocket accommodates at least five but no more than six amino acids.


Multimodal imaging of an acute presentation of ocular histoplasmosis syndrome in an immunocompetent patient.
Presumed ocular histoplasmosis syndrome (POHS) is a posterior segment disorder that is usually subclinical unless choroidal neovascular membrane (CNVM) develops. It is thought to be the sequela of a prior systemic infection with Histoplasma capsulatum, and evidence supporting this association is based on epidemiologic, animal, and few enucleation studies. Acute presentation of chorioretinal involvement during an initial histoplasmosis systemic infection in immunocompetent patients is rarely reported, presumably due to the usual lack of or minimal symptoms of both the systemic and ocular disease. We report on an immunocompetent male with choroidal lesions detected during disseminated histoplasmosis infection and characterize the lesions using multimodal imaging. A 17-year-old male presented when routine optometry screening detected two deep, yellowish-white lesions in the left fundus. Optical coherence tomography (OCT) imaging confirmed a choroidal mass with extension through Bruch's membrane into the subretinal space and a small amount of subretinal fluid. Fluorescein angiography was suggestive of CNVM. There were no clinical findings of intraocular inflammation, and the patient was initially lost to follow-up. Eight weeks after last follow-up, the patient presented to the emergency department with fatigue, mild respiratory symptoms, and abdominal pain for the last month. Imaging revealed a mediastinal mass with hilar extension and innumerable nodules throughout the lung and spleen. Serum Histoplasma IgM/IgG were positive, and biopsy of the mediastinal mass revealed Histoplasma organisms. The patient was treated with antifungals and discharged. The patient underwent an extensive immunologic evaluation while admitted, which did not reveal an underlying immunodeficiency. On last follow-up, the choroidal lesions were smaller and more consolidated, and the subretinal fluid had resolved. We present a patient with choroidal lesions in the setting of disseminated systemic histoplasmosis infection and characterize a lesion using multimodal imaging. The presentation of acute chorioretinal lesions in the setting of biopsy proven systemic Histoplasma infection supports H. capsulatum as the etiology of POHS.


Energetics of running in top-level marathon runners from Kenya.
On ten top-level Kenyan marathon runners (KA) plus nine European controls (EC, equivalent to KA), we measured maximal oxygen consumption (VO2max) and the energy cost of running (Cr) on track during training camps at moderate altitude, to better understand the KA dominance in the marathon. At each incremental running speed, steady-state oxygen consumption (VO2) was measured by telemetric metabolic cart, and lactate by electro-enzymatic method. The speed requiring VO2 = VO2max provided the maximal aerobic velocity (νmax). The energy cost of running was calculated by dividing net VO2 by the corresponding speed. The speed at lactate threshold (ν(ΘAN)) was computed from individual Lâ(b) versus speed curves. The sustainable VO2max fraction (Fd) at ν(ΘAN) (F(ΘAN)) was computed dividing nu(ΘAN) by νmax. The Fd for the marathon (Fmar) was determined as Fmar = 0.92 F(ΘAN). Overall, VO2max (64.9 ± 5.8 vs. 63.9 ± 3.7 ml kg(-1) min(-1)), νmax (5.55 ± 0.30 vs. 5.41 ± 0.29 m s(-1)) and Cr (3.64 ± 0.28 vs. 3.63 ± 0.31 J kg(-1) m(-1)) resulted the same in KA as in EC. In both groups, Cr increased linearly with the square of speed. F(ΘAN) was 0.896 ± 0.054 in KA and 0.909 ± 0.068 in EC; Fmar was 0.825 ± 0.050 in KA and 0.836 ± 0.062 in EC (NS). Accounting for altitude, running speed predictions from present data are close to actual running performances, if F(ΘAN) instead of Fmar is taken as index of Fd. In conclusion, both KA and EC did not have a very high VO2max, but had extremely high Fd, and low Cr, equal between them. The dominance of KA over EC cannot be explained on energetic grounds.


Pleth variability index during preoxygenation could predict anesthesia-induced hypotension: A prospective, observational study.
To determine whether changes in the pleth variability index (PVi) during preoxygenation with forced ventilation for 1 min could predict anesthesia-induced hypotension. Prospective, observational study. A tertiary teaching hospital. Ninety-six patients who underwent general anesthesia using total intravenous anesthesia were enrolled. Upon the patient's arrival at the preoperative waiting area, a PVi sensor was affixed to their fourth fingertip. For preoxygenation, forced ventilation of 8 breaths/min in a 1:2 inspiratory-expiratory ratio was conducted using the guidance of an audio file. One minute after preoxygenation, anesthetic administration was initiated. Blood pressure was measured for the next 15 min. We calculated the difference (dPVi) and percentage of change (%PVi) between the PVi values immediately before and after forced ventilation. Anesthesia-induced hypotension was defined as a mean arterial pressure of <60 mmHg within 15 min after the infusion of anesthetics. Overall, 87 patients were included in the final analysis. Anesthesia-induced hypotension occurred in 31 (35.6%) of the 87 patients. Receiver operating characteristic curve analyses identified a cut-off value of -2 for dPVi, with an area under the curve of 0.691 (95% confidence interval [CI], 0.564-0.818; P < 0.001) and a cut-off value of -7.6% for %PVi, with an area under the curve of 0.711 (95% CI, 0.589-0.832; P < 0.001). Further, multivariate logistic regression analysis showed that a low %PVi with an odds ratio of 9.856 (95% CI, 3.131-31.032; P < 0.001) was a significant determinant of anesthesia-induced hypotension. Hypotension frequently occurs during general anesthesia induction and can impact outcomes. Additionally, the percentage change in the PVi before and after preoxygenation using deep breathing can be used to predict anesthesia-induced hypotension.


B-type natriuretic peptide and N-terminal pro-BNP in the acute phase of Kawasaki disease.
This study was undertaken to identify factors correlating with plasma levels of B-type natriuretic peptide (BNP) and its N-terminal portion (NTpro BNP) in the acute phase of Kawasaki disease (KD). This study included 91 patients with KD treated at a hospital affiliated to Hamamatsu University School of Medicine between October 2003 and June 2011. We quantified BNP and NT-pro BNP in the acute phase. The BNP level was expressed as the NT-pro BNP level using the formula NT-pro BNP=9.080×BNP(0.923). We sought relationships between NT-pro BNP values and different clinical and laboratory data in the acute phase of KD. Of the 91 patients, 14 failed to respond to the initial intravenous immunoglobulins therapy. NTpro BNP levels were significantly higher in these nonresponders than in the responders (1689.3±1168.8 pg/ dL vs. 844.4±1276.3 pg/dL, P<0.001). Seventeen patients developed coronary artery lesions, but this was not associated with NT-proBNP levels. NT-pro BNP was positively correlated with CRP (r=0.421, P<0.001) and negatively correlated with the hematocrit (r=-0.206, P=0.050), Na value (r=-0.214, P=0.041) and albumin level (r=-0.345, P<0.001). Stepwise multiple linear regression analysis with NT-pro BNP as a dependent variable revealed significant correlations with CRP and albumin (beta=0.345, P=0.001; beta=-0.225, P=0.027). A high level of NT-pro BNP in acute phase KD is associated with systemic inflammatory responses and increased vascular permeability. The NT-pro BNP level is a useful marker to identify potential non-responders to IVIG among KD patients.


Influence of GYKI-13504, a new antioestrogen, on the responsiveness of isolated uterus removed from oestradiol pretreated rats to PGF2 alpha.
The responsiveness of the uteri of ovariectomized rats pretreated either with E2 or with a new antioestrogen, GYKI-13504 or with both agents simultaneously to PGF2 alpha was studied in vitro. The treatment with E2 caused a fortyfold reduction in the responsiveness of the uterus to PGF2 alpha. GYKI-13504 itself did not influence the sensitivity of this organ significantly, but inhibited the diminishing effect of E2.


Global Barriers to the Diagnosis of Multiple Sclerosis: Data From the Multiple Sclerosis International Federation Atlas of MS, Third Edition.
Recent data suggest increasing global prevalence of multiple sclerosis (MS). Early diagnosis of MS reduces the burden of disability-adjusted life years and associated health care costs. Yet diagnostic delays persist in MS care and even within national health care systems with robust resources, comprehensive registries, and MS subspecialist referral networks. The global prevalence and characteristics of barriers to expedited MS diagnosis, particularly in resource-restricted regions, have not been extensively studied. Recent revisions to MS diagnostic criteria demonstrate potential to facilitate earlier diagnosis, but global implementation remains largely unknown. The Multiple Sclerosis International Federation third edition of the Atlas of MS was a survey that assessed the current global state of diagnosis including adoption of MS diagnostic criteria; barriers to diagnosis with respect to the patient, health care provider, and health system; and existence of national guidelines or national standards for speed of MS diagnosis. Coordinators from 107 countries (representing approximately 82% of the world population), participated. Eighty-three percent reported at least 1 "major barrier" to early MS diagnosis. The most frequently reported barriers included the following: "lack of awareness of MS symptoms among general public" (68%), "lack of awareness of MS symptoms among health care professionals" (59%), and "lack of availability of health care professionals with knowledge to diagnose MS" (44%). One-third reported lack of "specialist medical equipment or diagnostic tests." Thirty-four percent reported the use of only 2017 McDonald criteria (McD-C) for diagnosis, and 79% reported 2017 McD-C as the "most commonly used criteria." Sixty-six percent reported at least 1 barrier to the adoption of 2017 McD-C, including "neurologists lack awareness or training" by 45%. There was no significant association between national guidelines pertaining to MS diagnosis or practice standards addressing the speed of diagnosis and presence of barriers to early MS diagnosis and implementation of 2017 McD-C. This study finds pervasive consistent global barriers to early diagnosis of MS. While these barriers reflected a lack of resources in many countries, data also suggest that interventions designed to develop and implement accessible education and training can provide cost-effective opportunities to improve access to early MS diagnosis.


Muscle-afferent projection to the sensorimotor cortex after voluntary movement and motor-point stimulation: an MEG study.
To investigate the projection of muscle afferents to the sensorimotor cortex after voluntary finger movement by using magnetoencephalography (MEG). The movement-evoked magnetic fields (MEFs) after voluntary index-finger extension were recorded by a 204-channel whole-head MEG system. Somatosensory-evoked magnetic fields (SEFs) were recorded after motor-point stimulation was applied to the right extensor indicis muscle by using a pair of wire electrodes. The MEF waveforms were observed at 35.8±9.7 ms after movement onset (MEF1). The most concentrated SEFs were identified at 78.7±5.6 ms (M70), and the onset latency of M70 was 39.0±5.5 ms after motor-point stimulation. The mean locations of the equivalent current dipoles (ECDs) of MEF1 and M70 were significantly medial and superior to that of N20m elicited by median-nerve stimulation. The ECD locations and directions of both MEF1 and M70 were concordant in the axial, coronal and sagittal planes. MEF1 and M70 might be elicited by muscle-afferent feedback following muscle contraction. In addition, these ECDs may be located in area 4. Motor-point stimulation is a useful tool for confirming the projection of muscle-afferent feedback to the sensorimotor cortex after voluntary movement.


Outcomes and prognostic factors for squamous cell carcinoma of the oral tongue in young adults: a single-institution case-matched analysis.
There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999-2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines.


Gonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection.
Hormones have wide-ranging effects throughout the nervous system, including the ability interact with and modulate many aspects of intracellular calcium regulation and calcium signaling. Indeed, these interactions specifically may help to explain the often opposing or paradoxical effects of hormones, such as their ability to both promote and prevent neuronal cell death during development, as well as reduce or exacerbate damage following an insult or injury in adulthood. Here, we review the basic mechanisms underlying intracellular calcium regulation-perhaps the most dynamic and flexible of all signaling molecules-and discuss how gonadal hormones might manipulate these mechanisms to coordinate diverse cellular responses and achieve disparate outcomes. Additional future research that specifically addresses questions of sex and hormone effects on calcium signaling at different ages will be critical to understanding hormone-mediated neuroprotection.


Effect of atorvastatin on erectile functions in comparison with regular tadalafil use. A prospective single-blind study.
Erectile dysfunction (ED) is a common problem for elderly males. Higher serum lipid levels have important role in the pathogenesis, and in this prospective randomized trial, it is aimed to identify the effect of atorvastatin on erectile functions in comparison with regular tadalafil use. 120 patients with a minimum 3-months history of moderate-to-severe ED were involved. The patients were randomized to receive atorvastatin 10 mg/day, tadalafil 20 mg 3 times/week or no medication. Baseline serum testosterone, lipid levels IEEF and NPT test were performed and repeated after 3 months of treatment, and the 3 groups were compared. Mean age of the whole population was 56 years (31-70). The 3 groups were well balanced for the baseline characteristics. Mean improvement of IIEF score was significantly higher in tadalafil group compared to atorvastatin (P = 0.01) and control group (P = 0.0001). Also atorvastatin showed significantly better improvement compared to control group (P = 0.001). Positive NPT test results in tadalafil group was significantly higher than atorvastatin group (25/40 (62.5%) vs. 16/41 (39%), P = 0.003) and compared to control group (25/40 (62.5%) vs. 3/39 (7.6%), P = 0.0001). At the same time, the difference between group 1 and group 3 was statistically significant (P = 0.001). Tadalafil 20 mg three times/week shows better results than 10 mg atorvastatin daily. Atorvastatin alone seems to improve EF compared to not using any medication, and this significance is more prominent in patients with supranormal serum lipid levels. Further studies with subgroups of different serum lipid levels should be conducted.


Descemet's membrane detachment associated with inadvertent viscoelastic injection in viscocanalostomy.
We report a case of Descemet's membrane detachment, a rare complication of viscocanalostomy. During the operation, the injection cannula was directed slightly oblique to the Schlemm's canal rather than parallel to it. Localized corneal whitening developed adjacent to the injection site during viscoelastic injection. One week postoperatively, corneal edema decreased and Descemet's membrane detachment was noted. Nine months after surgery, the cornea was clear while the Descemet's membrane detachment remained. And IOP was 19 mmHg without any medications. We think that improper cannula positioning during viscoelastic injection may cause Descemet's membrane detachment, a rare complication of viscocanalostomy.


The in vitro transcription-translation of DNA and RNA templates by extracts of Rhodopseudomonas sphaeroides. Optimization and comparison of template specificity with Escherichia coli extracts and in vivo synthesis.
A DNA-directed coupled transcription-translation system has been developed in cell-free extracts from the facultative phototroph, Rhodopseudomonas sphaeroides. The in vitro protein-synthesizing system was active when prepared from either chemoheterotrophically or photoheterotrophically grown cells. Optimal activity was dependent upon: use of extracts prepared freshly from early exponential phase cells, the method of cell breakage, and the length of preincubation of the extract (S-30), as well as the concentrations of S-30, template, and cations. The R. sphaeroides cell-free system was compared to one prepared from Escherichia coli. DNA templates tested included R. sphaeroides phage RS1 DNA and E. coli phages T4 and T7 DNA, as well as plasmids RSF1010, pBR322, pSL25 (a pBR322 derivative), and a chimeric plasmid of pSL25 and RSF1010. One RNA template, phage R17, was also employed to test translational fidelity. Transcriptional-translational specificity was observed between R. sphaeroides and E. coli and these observations are discussed in terms of differential gene expression among phylogenetically distinct groups of bacteria.


Step-advancement island flap for fingertip reconstruction.
An island flap is described for fingertip reconstruction, based on one neurovascular bundle. The design incorporates the stepladder principle, which ensures the provision of ample skin with full tactile sensibility in the required position, without the risk of longitudinal volar scarring and with good nail support when necessary. Fourteen such repairs have been carried out with satisfactory results and no complications.


Effects of Nordic walking on cardiovascular performance and quality of life in coronary artery disease.
Cardiometabolic effects of physical exercise depend on its intensity, duration, and type. Conventional cardiovascular rehabilitation (CCVR) programs have significant advantages, but non-conventional activities such as Nordic walking (NW) may offer additional health benefits. The aim of this study was to determine the feasibility and effectiveness of NW on cardiovascular performance and quality of life in patients with coronary artery disease (CAD) compared to a CCVR program. This was a pseudo-randomized, prospective, single-blinded, parallel-group trial. The study was conducted at a resort/spa type facility located in a mountainous natural environment, 650 meters above sea level. Eighty-three CAD patients were allocated to either a Nordic walking or a control group. The NW group (N.=53; age 59.1±7.0 years) underwent a three-week outdoor exercise program consisting of 40 minutes of walking four-times per week, whereas the controls performed traditional walking instead of NW. A patient's prescribed exercise intensity was according to exertion tolerance within 50-70% of peak oxygen consumption (VO<inf>2max</inf>); rating of perceived exertion 'mild/moderate' (12 to 14 points) on the 0-20 Borg Scale. Primary endpoint: cardiovascular and functional performance (exercise ergometry [EE], metabolic equivalent of tasks [METs], ejection fraction [EF], Six-Minute Walking Test [6MWT]). Secondary endpoint was quality of life (Short-Form 36 Health Survey). Statistical analysis was performed by generalized estimating equations with Cohen's d effect size (ES). NW led to higher cardiovascular performance compared to CCVR (ΔEE: +11.0% vs. +3.2%, small ES; ΔMETs: +9.8% vs. +1.5%, medium ES) and better functional performance (Δ6MWT: +8.3% vs. +5.1%, small ES). No significant differences were detected in EF (P=0.240) and SF-36 (PCS, P=0.425; MCS, P=0.400). A three-week NW training program had clinically important effects, above and beyond CCVR, on cardiovascular and functional performance in CAD patients. Nordic walking is an accessible, safe, and effective low-threshold cardiac rehabilitation exercise training modality that seems to be particularly well-suited for people with limited functional and motivational capacities.


Examination of the premature infant.
Ophthalmoscopic examination of the premature infant requires binocular indirect ophthalmoscopy, use of an eyelid speculum, and wide pupillary dilatation. Normal and pathologic features unique to the infant eye often are encountered. Familiarity with these features is essential for accurate diagnosis and prevention of unnecessary therapeutic intervention. Supplemental oxygen is the mainstay of supportive therapy for idiopathic respiratory distress syndrome, a common cause for morbidity in premature infants. Arterial oxygen monitoring is essential for survival and for prevention of retrolental fibroplasia, but precise arterial oxygen levels associated with development of retrolental fibroplasia have not been established.


Prevention of chronic complications of diabetes mellitus according to complexity.
To assess the prevention by primary health care providers of chronic complications of diabetes mellitus according to the complex thinking theoretical approach. Evaluative research based on the complex thinking theoretical approach. The following techniques for data collection were used: interviews with 38 participants; observation in collective and individual appointments; and analysis of medical records of people with diabetes. The triangulation applied for data analysis was the ATLAS.ti software. The prevention and management of chronic complications of diabetes did not meet the requirements set forth by ministerial public policies aimed at this population. Systematic monitoring to prevention of chronic complications showed significant gaps. Primary health care did not consider preventive actions for diabetes mellitus complications. This context was marked by disjunctive, fragmented, and dissociated practices types of care targeted to the totality of the assisted people. Avaliar a prevenção de complicações crônicas do diabetes mellitus a luz do referencial teórico do Pensamento Complexo por integrantes da atenção primária à saúde. Pesquisa avaliativa, que teve como referencial teórico o Pensamento Complexo. Como técnicas de coleta de dados foram utilizadas: entrevista com 38 participantes; observação nos atendimentos coletivos e individuais;e análise em 25 prontuários de pessoas com diabetes. A triangulação subsidiou a análise de dados que teve auxílio do software ATLAS.ti. A prevenção e o manejo das complicações crônicas do diabetes não atendiam ao estabelecido nas políticas públicas ministeriais destinadas a esse público. O acompanhamento sistematizado para controle da prevenção das complicações crônicas apresentou importantes lacunas. A assistência na atenção primária não contemplava ações de prevenção de complicação do diabetes mellitus. Esse contexto era por marcado por práticas disjuntivas, fragmentadas e dissociadas de uma assistência que visa a totalidade das pessoas assistidas.


[The use of the infraclavicular plexus catheter for treatment of perioperative and chronic pain].
The aim of this prospective study was to evaluate the vertical infraclavicular approach to the brachial plexus for the insertion of a catheter to achieve continuous analgesia in postoperative patients and patients with chronic upper limb pain. The brachial plexus was identified using the technique described by Kilka et al. and a flexible catheter (diameter 0.85 mm) was introduced 3-5 cm into the perineural sheath via the punction cannula. Regional analgesia was achieved by intermittent injection of local anaesthetic agent. Placement of the catheter, duration and effectiveness of treatment, complications and reasons for catheter removal were recorded using a standard protocol. A total number of 226 plexus catheters were placed in 210 patients. Consecutive regional analgesia for at least 48 h was possible in 88%. Analgesia was sufficient in 76% of patients up to the time of catheter removal. The median (minimum-maximum) duration of catheterisation in the whole collective was 7 days (1-240) and 11 days in patients with chronic pain. Almost 30% of the patients were treated for 10 days or longer and 4.4% were treated for 1 month or longer. Major complications occurred in only three cases, while technical problems and minor complications (redness at puncture site) occurred in 10% of cases. The placement of an infraclavicular plexus catheter is a suitable method for pain management in the upper limb. This approach may have advantages in patients with severe injuries who cannot abduct the arm. Our results are encouraging in terms of catheterisation time, patient comfort and incidence of complications.


Opioid antagonist effects of dezocine in opioid-dependent humans.
Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.


Long-term follow-up after ileocaecal continent cutaneous urinary diversion (Mainz I pouch): A retrospective study of a monocentric experience.
To assess the long-term follow-up after ileocaecal continent cutaneous reservoir (ICCR) and to review the late complications. In all, 756 patients underwent an ICCR in our department, with long-term follow-up data available in 50 patients. The inclusion criterion was ICCR regardless of the indication and the exclusion criteria were orthotopic neobladder or other continent urinary diversions not performed with the ileocaecum. Patients were followed to record primary outcomes and late complications. Complications were stratified according to the Clavien-Dindo classification. The mean patient age was 44 years and pelvic malignancies were the first indication for urinary diversion. The mean (range) follow-up was 19 (9-36) years. A stoma stenosis was the most frequent outlet-related complication requiring re-intervention, followed by ischaemic outlet degeneration, and stoma incontinence. Six renal units (RUs) developed obstruction at the anastomotic site and were managed by open surgery. Three RUs had to be removed due to deterioration. A dederivation was necessary in three patients (6%). The ICCR is a safe and established technique when an orthotopic pouch is impossible. The long-term follow-up shows acceptable complication rates and satisfactory continence conditions. However, large population studies are necessary to confirm this observation.


An exploratory study of sleep quality and quantity in children with causal variants in SYNGAP1, an autism risk gene.
Sleep disturbances are reported in 62% of children with SYNGAP1-Intellectual Disability (SYNGAP1-ID), a rare neurodevelopmental disorder characterized by intellectual disability, epilepsy, autism spectrum disorder (ASD), sensory and behavioral challenges. Although Children's Sleep Habits Questionnaire (CSHQ) scores are elevated in children with SYNGAP1-ID factors that predict sleep disturbance are not well understood. The goal of this study is to identify predictors of sleep problems. Parents of 21 children with SYNGAP1-ID completed questionnaires, and 6 children wore the Actiwatch2 for 14 continuous days. Non-parametric analysis of psychometric scales and actigraphy data were performed. Actigraphy derived sleep parameters were compared to controls and rest activity rhythms were assessed using arctools an open-source R package. CSHQ total sleep scores in children with SYNGAP1-ID and ASD were not different from children with SYNGAP1 without ASD (p = 0.61). Sleep anxiety (β 1.646, 95% CI 0.9566 to 2.336) and parasomnias (β 0.6294, 95% CI 0.06423 to 1.195) were strong predictors of bedtime resistance (R2 = 0.767, p < 0.001). The sedentary to active transition probability during the 12-18 h epoch (β = 0.004, p = 0.008, R2 = 0.85) and the duration of the active bout during the 18-24 h epoch (β = 0.166, p = 0.029, R2 = 0.74) were strong predictors of total sleep disturbance. The CSHQ may be a reliable measure of sleep difficulties in children with SYNGAP1-ID. Sleep anxiety, parasomnias and difficulty winding-down are significant contributors to sleep disturbances.


Seed production and seed predation in a patchy and time-varying environment. Dynamics of a milkweed - tephritid fly system.
Vincetoxicum hirundinaria is a longlived perennial herb. Its pod production was measured during seven years in about 40 small isolated patches in two study areas in southeastern Sweden. Total pod production in the two areas varied synchronously and up to about 200 times between years. This variation was mainly due to drought conditions as determined by the interplay of weather (sunshine h) and site characteristics.Populations of a univoltine tephritid fly, euphranta connexa, whose larva feeds on V. hirundinaria seeds in the maturing pods, were monitored for five and seven years in the two study areas respectively. Larval fly populations in the two areas varied 30 and 50-fold between years, with highs in years when pods were abundant and lows when pods were scarce. The percentage of pods attacked by E. connexa, however, varied in the opposite direction, with very high attack rates (about 100%) when pods were scarce and low rates (down to 10-20%) when pods were common. Thus the temporal tracking of food resources by E. connexa was poor, resulting in yearly variations in the amount of unattacked pods (and seeds) being about 2,00-fold.Many host plant patches were small and totally without pods in some years, causing frequent local extinctions of E. connexa. Patches were, however, readily colonized in later years when pods appeared again. Low overall attack rates in certain years were thus only to a minor extent explainable by host plant patches being uncolonized by the fly. The efficient spatial tracking of resources by the fly population allows this population system to be analyzed largely in terms of its temporal dynamics.Although E. connexa populations often exploit only a minor part of their potential larval resources, the rate of population change was closely correlated with these resources expressed on a per capita basis. Natural enemies only have negligible effects on E. connexa population trends. In this population system the herbivore (seed predator) population is thus controlled by its food resources, but weather-imposed temporal variations in resource set are too large for the herbivore population to closely track its resource base. This temporal tracking inertia has important implications for the long-term production of healthy seeds.


Mechanistic model of myocardial energy metabolism under normal and ischemic conditions.
A moderate reduction in coronary blood flow results in decreased myocardial oxygen consumption, accelerated glycolysis, decreased pyruvate oxidation, and lactate accumulation. To quantitatively understand cardiac metabolism during ischemia, we have developed a mechanistic, mathematical model based on biochemical mass balances and reaction kinetics in cardiac cells. By numerical solution of model equations, computer simulations showed the dynamic responses in glucose, fatty acid, glucose-6-phosphate, glycogen, triglyceride, pyruvate, lactate, acetyl-CoA, and free-CoA as well as CO2, O2, phosphocreatine/creatine, nicotinamide adenine dinucleotide (reduced form)/nicotinamide adenine dinucleotide (oxidized form) (NADH/NAD+), and adenosine diphosphate/adenosine triphosphate (ADP/ATP). When myocardial ischemia was simulated by a 60% reduction in coronary blood flow, the model generated myocardial concentrations, uptakes, and fluxes that were consistent with experimental data from in vivo pig studies. After 60 min of ischemia the concentrations of glycogen, phosphocreatine, and ATP were decreased by 60%, 75%, and 50%, respectively. With the onset of ischemia, myocardial lactate concentration increased and the myocardium switched from net consumer to net producer of lactate. Our model predicted a rapid 13-fold increase in NADH/NAD+, but only a twofold increase in the ratio of acetyl-CoA to free-CoA. These findings are consistent with the concept that pyruvate oxidation is inhibited during ischemia partially by the rise in NADH/NAD+.


Regulatory Peptides in Plants.
Many different peptides regulating cell differentiation, growth, and development are found in plants. Peptides participate in regulation of plant ontogenesis starting from pollination, pollen tube growth, and the very early stages of embryogenesis, including formation of embryo and endosperm. They direct differentiation of meristematic stem cells, formation of tissues and individual organs, take part in regulation of aging, fruit maturation, and abscission of plant parts associated with apoptosis. Biological activity of peptides is observed at very low concentrations, and it has mainly signal nature and hormonal character. "Mature" peptides appear mainly due to processing of protein precursors with (or without) additional enzymatic modifications. Plant peptides differ in origin, structure, and functional properties. Their specific action is due to binding with respective receptors and interactions with various proteins and other factors. Peptides can also regulate physiological functions by direct peptide-protein interactions. Peptide action is coordinated with the action of known phytohormones (auxins, cytokinins, and others); thus, peptides control phytohormonal signal pathways.


Effects of sleep on a high-heat capacity mattress on sleep stages, EEG power spectra, cardiac interbeat intervals and body temperatures in healthy middle-aged men‡.
This study deals with the question whether a slow (non-disturbing) reduction of core body temperature (CBT) during sleep increases sleep stage N3 and EEG slow wave energy (SWE) and leads to a slowing of heart rate in humans. Thirty-two healthy male subjects with a mean ± SD age 46 ± 4 years and body mass index 25.2 ± 1.8 kg/m2. A high-heat capacity mattress (HM) was used to lower body temperatures in sleep and was compared to a conventional low-heat capacity mattress (LM) in a double-blinded fashion. Polysomnography was performed accompanied by measurements of skin-, core body- and mattress surface-temperatures, and heart rate. EEG power spectral analyses were carried out using Fast Fourier Transform. Interbeat intervals were derived from the electrocardiogram. The HM led to a larger decline in CBT, mediated through higher heat conduction from the core via the proximal back skin onto the mattress together with reduced heart rate. These effects occurred together with a significant increase in sleep stage N3 and standardized slow wave energy (sSWE, 0.791-4.297 Hz) accumulated in NREM sleep. In the 2nd half of the night sSWE increase was significantly correlated with body temperature changes, for example with CBT decline in the same phase. A HM subtly decreases CBT, leading to an increased amount of sleep stage N3 and of sSWE, as well as a slowing of heart rate.


The relationships between hematogram and metabolic syndrome in elderly subgroups: A Taiwan cohort study.
Abnormal hematogram components could predict future metabolic syndrome (MetS) and diabetes. However, there was no study focusing on the subgroups of the elderly. In this ten-year longitudinal study, we investigated the association between hematogram components, future MetS and diabetes in the elderly. Subjects above 65 years were divided into three groups by age (young old: ≧65 and <75, old-old: ≧75 and <85 and oldest-old ≧85).By using multiple logistic regression, the hazard ratio (HR) of higher hemoglobin (Hb), white blood cell count (WBCC) and platelet (PLT) to have future MetS and diabetes were evaluated. There were 15169 subjects in the young-old group, 3536 in the old-old group and 202 in the oldest-old group, respectively. After 10 years follow-up, only higher WBCC and Hb levels (>5.0×10(3), 15 g/dL, respectively) was correlated to future MetS in young-old men (adjusted HR: 1.242, 1.166, respectively). In addition, higher Hb (>13.7 g/dL) was originally associated with future MetS in young-old and old-old women but failed in adjusted HR. Moreover, the PLT did not correlate with any of the endpoints. Finally, higher chances of diabetes could be noted with higher WBCC in both men and women (adjusted HR: 1.404, 1.206, respectively). The associations between hematogram and future MetS were different in each subgroup of the elderly. Higher WBCC and Hb levels could predict future MetS in young-old men. Moreover, Higher WBCC is positively correlated with future diabetes in both young-old men and women.


Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection.
Plasmacytoid dendritic cells (pDC) are the major source of type I interferons (IFN-I) during viral infections, in response to triggering of endosomal Toll-like receptors (TLRs) 7 or 9 by viral single-stranded RNA or unmethylated CpG DNA, respectively. Synthetic ligands have been used to disentangle the underlying signaling pathways. The adaptor protein AP3 is necessary to transport molecular complexes of TLRs, synthetic CpG DNA, and MyD88 into endosomal compartments allowing interferon regulatory factor 7 (IRF7) recruitment whose phosphorylation then initiates IFN-I production. High basal expression of IRF7 by pDC and its further enhancement by positive IFN-I feedback signaling appear to be necessary for robust cytokine production. In contrast, we show here that in vivo during mouse cytomegalovirus (MCMV) infection pDC produce high amounts of IFN-I downstream of the TLR9-to-MyD88-to-IRF7 signaling pathway without requiring IFN-I positive feedback, high IRF7 expression, or AP3-driven endosomal routing of TLRs. Hence, the current model of the molecular requirements for professional IFN-I production by pDC, established by using synthetic TLR ligands, does not strictly apply to a physiological viral infection.


Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis.
The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. A three-year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13-5.10) and showed moderate discrimination (c-statistic: 0.685; 0.614-0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow-up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.


Strategies for handling missing clinical data for automated surgical site infection detection from the electronic health record.
Proper handling of missing data is important for many secondary uses of electronic health record (EHR) data. Data imputation methods can be used to handle missing data, but their use for analyzing EHR data is limited and specific efficacy for postoperative complication detection is unclear. Several data imputation methods were used to develop data models for automated detection of three types (i.e., superficial, deep, and organ space) of surgical site infection (SSI) and overall SSI using American College of Surgeons National Surgical Quality Improvement Project (NSQIP) Registry 30-day SSI occurrence data as a reference standard. Overall, models with missing data imputation almost always outperformed reference models without imputation that included only cases with complete data for detection of SSI overall achieving very good average area under the curve values. Missing data imputation appears to be an effective means for improving postoperative SSI detection using EHR clinical data.


Adaptation and Validation of the Shame Questionnaire Among Ugandan Youth Living with HIV.
The purpose of this study was to adapt and validate a measure of HIV-related shame, the Shame Questionnaire (SQ), among Ugandan youth living with HIV. Culturally relevant, reliable and valid measurement is critical in the accurate assessment of HIV-related shame (a painful internalized emotion encompassing feelings that the self is damaged and defective) on psychosocial functioning, as well as the determination of the efficacy of interventions among youth living with HIV in sub-Saharan Africa. We utilized qualitative (i.e., cognitive interviews; N = 31) and quantitative (i.e., classical test theory and item response theory; N = 150) methods to establish, content, criterion and construct validity of the SQ. Cognitive interviews resulted in the revision in the wording of 2 out of 8 SQ items. Participants who endorsed having shame had statistically significant higher SQ scores than participants who did not endorse having shame (p < 0.001), suggesting criterion validity. We found a statistically significant positive relationship between SQ scores and average trauma symptom scores among participants (p < 0.001), also suggesting criterion validity. Finally, we found construct validity with discrimination parameters of the graded response IRT model all in the high range with a wide range of difficulty parameters across the 8 items of the SQ. Overall our results suggest that the SQ is a contextually relevant, valid and reliable assessment tool among Ugandan youth living with HIV. Findings provide support for the utilization of qualitative and quantitative methods in the adaptation of measures for cross-cultural use in order to maintain validity and contextual relevance.


An ultrastructural study of cryofractured myocardial cells with special attention to the relationship between mitochondria and sarcoplasmic reticulum.
A comparative study of various cryofracturing techniques has been conducted on the mammalian myocardial cell. Quench freezing of fresh or fixed tissue in melting Freon 22 resulted in severe cellular damage due to ice crystallization. Fixation with Karnovsky's fixative prior to quenching had no modifying effect on the size and distribution of the ice crystals. The crystals were orientated primarily in the direction of the long axis of the myofibrils, manifested as empty tube-like structures in the scanning electron microscope (SEM). Regular cross-bridging often seen at the Z-band levels indicated that ice crystals, at least in some portions of the cells, were confined within the sarcomere. Within the same cell the size of the ice crystals could vary considerably. Treatment of the tissue with polyvinylpyrrolidone (PVP) prior to rapid freezing had no noticeable cryoprotective effect. The surface of the thin layer of PVP surrounding the freeze dried tissue appeared amorphous in the SEM. However, the first evidence of ice crystallization was found a few micrometers under the surface. The freezing artefacts were completely circumvented if the cryofracturing was carried out on ethanol-impregnated or on critical point dried material. While the first method resulted in a smooth fracture plane passing through the cell structures, the intracellular fracture plane of the critical point dried material followed the surface of the cell organelles. Separation of the cell organelles caused by freezing or by critical point drying revealed thread-like structures extending from the mitochondrial surface. Re-examination of SEM-processed material in the transmission electron microscope (TEM) revealed that these structures were part of the sarcoplasmic reticulum (SR), and that a close contact between the SR and the outer mitochondrial membrane existed. TEM of conventional prepared material revealed that strands of electron-dense material, here named 'mito-reticular junctional fibres', bridged the narrow gap between the mitochondrial surface and the SR. It is suggested that these fibres have a specific anchoring function.


Environmental and anthropic variabilities at Guanabara Bay (Brazil): A comparative perspective of metal depositions in different time scales during the last 5,500 yrs.
The determination of age-dated metal sediment accumulation rates in a representative South American bay is able to portray the dimension of human impacts during the colonial occupation and industrial periods. Many studies have assessed metal distribution and chronology at Guanabara Bay, in Brazil. However, understanding natural variabilities associated to paleoclimatic changes and comparing these natural variabilities to anthropogenic processes are not well established to date. Accurate geochronological control integrating ages determined by 210Pb and 14C chronologies through an exponential spline fit model allowed for a precise definition of changes associated to the holocene marine transgression, as well as the colonial period, leading to intense land use changes, and the industrial period. The reference values of the system were defined based on their concentrations and the accumulation rates of ecotoxicologically important metals. Al, Ba, Fe, Cd, Cu, Cr, Li, Ni, Mn, Pb, Si, Ti, V, and Zn distributions were determined in a Guanabara Bay core (BG-28) by the EPA 3051 method. Elemental distribution profile assessment allowed for the identification of variabilities associated to weathering processes, predominantly of lithogenic origin, mainly for Al, Ba, Fe, Li, Si, and V. Weathering processes occurred simultaneously to land use changes in the drainage basin since the colonial period, at 400 cal yr BP, and during the industrial period, mainly after the 1960s, denoted by Cd, Cr, Cu, Mn, Pb and Zn increases. The highest average metal enrichment values metals associated to industrial processes reached 5.95, with 119.1-fold higher accumulation rates than the background accumulation values observed between 4200 and 500 cal yr BP.


Differences in characteristics of Medicare patients treated by ophthalmologists and optometrists.
To quantify differences in the age, gender, race, and clinical complexity of Medicare beneficiaries treated by ophthalmologists and optometrists in each of the United States. Cross-sectional study based on publicly accessible Medicare payment and utilization data from 2012 through 2017. For each ophthalmic and optometric provider, demographic information of treated Medicare beneficiaries was obtained from the Medicare Provider Utilization and Payment Data from the Centers for Medicare and Medicaid Services (CMS) for the years 2012 through 2017. Clinical complexity was defined using CMS Hierarchical Condition Category (HCC) coding. From 2012 through 2017, ophthalmologists in every state treated statistically significantly older beneficiaries, with the greatest difference (4.99 years in 2014) between provider groups seen in Rhode Island. In most states there was no gender difference among patients treated by the providers but in 46 states ophthalmologists saw a more racially diverse group of beneficiaries. HCC risk score analysis demonstrated that ophthalmologists in all 50 states saw more medically complex beneficiaries and the differences were statistically significant in 47 states throughout all six years. Although there are regional variations in the characteristics of patients treated by ophthalmologists and optometrists, ophthalmologists throughout the United States manage older, more racially diverse, and more medically complex Medicare beneficiaries.


High-throughput deep learning variant effect prediction with Sequence UNET.
Understanding coding mutations is important for many applications in biology and medicine but the vast mutation space makes comprehensive experimental characterisation impossible. Current predictors are often computationally intensive and difficult to scale, including recent deep learning models. We introduce Sequence UNET, a highly scalable deep learning architecture that classifies and predicts variant frequency from sequence alone using multi-scale representations from a fully convolutional compression/expansion architecture. It achieves comparable pathogenicity prediction to recent methods. We demonstrate scalability by analysing 8.3B variants in 904,134 proteins detected through large-scale proteomics. Sequence UNET runs on modest hardware with a simple Python package.


What is the role of modifiable environmental and lifestyle risk factors in young onset dementia?
Young onset dementia (YOD) is associated with significant costs and burden, but its cause is poorly understood. The aim of this review was to determine whether environmental and lifestyle factors are associated with risk for non-autosomal dominant degenerative and vascular YOD. Academic databases were searched to March 2015 for studies assessing the impact of modifiable factors (e.g. education, cardiovascular illness, psychiatric illness, alcohol use) in participants under 65 years at symptom onset. Cardiovascular illness, traumatic brain injury, psychiatric illness, heavy alcohol use and estrogen-related factors were identified as potential risk factors for YOD. Evidence for education, childhood development, smoking and heavy metal exposure was inconsistent or of poor quality. A dose-response relationship was found between cumulative and/or increasing severity of exposure and risk for YOD. Environmental and lifestyle risk factors may be relevant to YOD, particularly with severe or cumulative exposure. More high quality research is required to confirm which factors confer risk and when.


Spatially localized sono-photoacoutic activation of phase-change contrast agents.
Sono-photoacoustic (SPA) activation lowers the threshold of phase-change contrast agents by timing a laser shot to coincide with the arrival of an acoustic wave at a region of interest. The combination of photothermal heating from optical absorption and negative pressure from the acoustic wave greatly reduces the droplet's combined vaporization threshold compared to using laser energy or acoustic energy alone. In previous studies, SPA imaging used a broadly illuminated optical pulse combined with plane wave acoustic pulses transmitted from a linear ultrasound array. Acoustic plane waves cover a wide lateral field of view, enabling direct visualization of the contrast agent distribution. In contrast, we demonstrate here that localized SPA activation is possible using electronically steered/focused ultrasound pulses. The focused SPA activation region is defined axially by the number of cycles in the acoustic pulse and laterally by the acoustic beam width. By reducing the spot size and enabling rapid electronic steering, complex activation patterns are possible, which may be particularly useful in therapeutic applications.


Mortality and neurologic, mental, and psychomotor development at 2 years in infants born less than 27 weeks' gestation: the Leiden follow-up project on prematurity.
To determine the outcome of infants with a gestational age (GA) <27 weeks, born in the mid-1990s. Regional, prospective study; part of the Leiden Follow-Up Project on Prematurity. Three health regions in The Netherlands. A total of 266 live born infants (1996/1997) with GA <32 weeks; 46 infants were <27 weeks. Neurologic examination (according to Hempel) and assessment of mental and psychomotor development using the Bayley Scales of Infant Development I, at the corrected age of 2 years. Mortality was 35% (16 of 46) <27 weeks, compared with 6% (14 of 220) in infants with GA 27 to 32 weeks; withdrawal of treatment in 60% and 43%, respectively. Below 27 weeks mortality was higher after extra-uterine transport and pregnancy induction. Neonatal morbidity was higher in infants <27 weeks compared with infants 27 to 32 weeks. Below 27 weeks postnatal use of dexamethasone and being hospitalized at term were associated with abnormal neurologic outcome; there was a higher incidence in (mild) mental developmental delay compared with the older infants. Adverse outcome (dead or abnormal neurologic, psychomotor, or mental development) in infants 23 to 24, 25, 26, and 27 to 32 weeks GA was, respectively, 92% (11 of 12), 64% (7 of 11), 35% (8 of 23), and 18% (40 of 220). Mortality and neonatal morbidity were higher in infants with GA <27 weeks compared with infants born between 27 and 32 weeks. The high adverse outcome of infants <25 weeks suggests that one should carefully weigh whether or not to aggressively resuscitate and treat these extremely premature infants.


Vulnerability to climate change of species in protected areas in Thailand.
Although 23% of Thailand's land is in protected areas, these are vulnerable to climate change. We used spatial distribution modelling for 866 vertebrate and 591 plant species to understand potential climate change impacts on species in protected areas. Most mammals, birds, and plants were projected to decline by 2070, but most amphibians and reptiles were projected to increase. By 2070 under RCP8.5, 54% of modeled species will be threatened and 11 nationally extinct. However, SDMs are sensitive to truncation of the climate space currently occupied by habitat loss and hunting, and apparent truncation by data limitations. In Thailand, lowland forest clearance has biased records for forest-dependent species to cooler uplands (> 250 m a.s.l.) and hunting has confined larger vertebrates to well-protected areas. In contrast, available data is biased towards lowland non-forest taxa for amphibians and reptiles. Niche truncation may therefore have resulted in overestimation of vulnerability for some mammal and plant species, while data limitations have likely led to underestimation of the threat to forest-dependent amphibians and reptiles. In view of the certainty of climate change but the many uncertainties regarding biological responses, we recommend regular, long-term monitoring of species and communities to detect early signals of climate change impacts.


Longitudinal relations of sleep quality with depressive symptoms, diabetes distress and self-efficacy in young people with type 1 diabetes.
To examine the longitudinal, bidirectional associations of sleep quality with depressive symptoms, diabetes-specific distress and diabetes management self-efficacy among adolescents and young adults with type 1 diabetes. Cross-lagged analyses used baseline, three-, six- and nine-month data from a randomized trial among 60 young people. Self-report measures included the Pittsburgh Sleep Quality Index, Center for Epidemiological Studies - Depressed Mood scale, Problem Areas in Diabetes Teen version, and Diabetes Management Self-efficacy Scale. Lower sleep quality at baseline was associated with higher three-month depressive symptoms (b = 0.21, p = 0.005) and lower diabetes self-efficacy (b = -0.18, p = 0.014), but not diabetes distress (b = 0.06, p = 0.403). Similar patterns were found at six and nine months. Three-month psychological functioning was not associated with six-month sleep quality. Among adolescents and young adults with type 1 diabetes, lower sleep quality predicted subsequent depressive symptoms and lower diabetes self-efficacy rather than vice versa. Sleep deserves a central place in diabetes care.