Tanshinone IIA, the key compound in Salvia miltiorrhiza, improves cognitive impairment by upregulating Aβ-degrading enzymes in APP/PS1 mice.
In Alzheimer's disease (AD), amyloid-beta (Aβ) plays a crucial role in pathogenesis. Clearing Aβ from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aβ. Molecular docking result showed that Tan IIA might block AD by upregulating Aβ-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aβ-degrading enzymes.


[Long-term outcome after implantation of various intraocular lenses through a corneal tunnel].
A prospective, randomized study was carried out to evaluate functional and biomicroscopic long-term results of different posterior chamber intraocular lenses (IOLs) over a period of two years after clear corneal cataract surgery. 2 years after phacoemulsification through a temporal two-step clear corneal incision a total of 67 patients were examined. In 26 eyes (group A) a foldable plate-haptic silicone IOL (Chiron Adatomed, C10), in 25 eyes (group B) a foldable disc silicone IOL (Chiron Adatomed, 90D) had been implanted through a 3.5 (group A) or 4 mm (group B) corneal incision using a cartridge injector. In 16 eyes (group C) a one-piece PMMA-IOL (Pharmacia & Upjohn, 809C) had been implanted through a 5 mm incision. All eyes underwent functional and biomicroscopic examinations, as well as computerized videokeratographic analysis to obtain corneal topography data. In group A uncorrected visual acuity valued 0.64 (+/-0.29 SD), in group B 0.59 (+/-0.24) and in group C 0.56 (+/-0.27). Median of uncorrected visual acuity was 0.6 for all groups. Corrected visual acuity was 0.81 (+/-0.29) in group A, 0.8 (+/-0.25) in group B and 0.83 (+/-0.3) in group C. Intraocular pressure (mm Hg) was 13 (+/-2.5) in group A, 14.7 (+/-2) in group B and 15.1 (+/-2.5) in group C. Fibrosis of the anterior capsular rim occurred in 42% of the cases. One eye demonstrated folds in the posterior capsule (group B). Posterior capsular opacification valued 11.9% for all groups. In one eye a Nd:YAG-capsulotomy had already been performed. In group A a decentration of more than 1 mm was objected in one case, in group B in two cases and in group C in one case, but no patient complained about any functional impairment. Two years postoperatively, no signs of a re-flattening in the incision area could be detected using difference mapping tools in the videokeratographic analysis. Two years after implantation of foldable silicone IOLs and PMMA-IOLs via a temporal clear corneal tunnel incision after phacoemulsification only slight functional and morphologic differences between the three IOL-types could be observed.


Studies of gene expression and activity of hexokinase, phosphofructokinase and glycogen synthase in human skeletal muscle in states of altered insulin-stimulated glucose metabolism.
When whole body insulin-stimulated glucose disposal rate is measured in man applying the euglycaemic, hyperinsulinaemic clamp technique it has been shown that approximately 75% of glucose is taken up by skeletal muscle. After the initial transport step, glucose is rapidly phosphorylated to glucose-6-phosphate and routed into the major pathways of either glucose storage as glycogen or the glycolytic/tricarboxylic acid pathway. Glucose uptake in skeletal muscle involves-the activity of specific glucose transporters and hexokinases, whereas, phosphofructokinase and glycogen synthase hold critical roles in glucose oxidation/glycolysis and glucose storage, respectively. Glucose transporters and glycogen synthase activities are directly and acutely stimulated by insulin whereas the activities of hexokinases and phosphofructokinase may primarily be allosterically regulated. The aim of the review is to discuss our present knowledge of the activities and gene expression of hexokinase II (HKII), phosphofructokinase (PFK) and glycogen synthase (GS) in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. My own experimental studies have comprised patients with disorders characterized by insulin resistance like non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) before and after therapeutic interventions, patients with microvascular angina and patients with severe insulin resistant diabetes mellitus and congenital muscle fiber type disproportion myopathy as well as athletes who are in a state of improved insulin sensitivity. By applying the glucose insulin clamp method in combination with nuclear magnetic resonance 31P spectroscopy to normoglycaemic or hyperglycaemic insulin resistant subjects impairment of insulin-stimulated glucose transport and/or phosphorylation in skeletal muscle has been shown. In states characterized by insulin resistance but normoglycaemia, the activity of HKII measured in needle revealed any genetic variability that contributes to explain the decreased muscle levels of GS mRNA or the decreased activity and activation of muscle GS in NIDDM patients and their glucose tolerant but insulin resistant relatives. Thus, the causes of impaired insulin-stimulated glycogen synthesis of skeletal muscle in normoglycaemic insulin resistant subjects are likely to be found in the insulin signalling network proximal to the GS protein. In insulin resistant diabetic patients the impact of these yet unknown abnormalities may be accentuated by the prevailing hyperglycaemia and hyperlipidaemia. Endurance training in young healthy subjects results in improved insulin-stimulated glucose disposal rates, predominantly due to an increased glycogen synthesis rate in muscle, which is paralleled by an increased total GS activity, increased GS mRNA levels and enhanced insulin-stimulated activation of GS. These changes are probably due to local contraction-dependent mechanisms. Likewise, one-legged exercise training has been reported to increase the basal concentration of muscle GS mRNA in NIDDM patients to a level similar to that seen in control subjects although insulin-stimulated glucose disposal rates remain reduced in NIDDM patients. In the insulin resistant states examined so far, basal and insulin-stimulated glucose oxidation rate at the whole body level and PFK activity in muscle are normal. In parallel, no changes have been found in skeletal muscle levels of PFK mRNA and immunoreactive protein in NIDDM or IDDM patients. In endurance trained subjects insulin-stimulated whole body glucose oxidation rate is often increased. However, depending on the intensity and frequency, physical exercise may induce an increased, a decreased or an unaltered level of muscle PFK activity. In athletes the muscle PFK mRNA is similar to what is found in sedentary subjects whereas the immunoreactive PFK protein concentration is decreased.


[Keratotic pseudoepitheliomatous and micaceous balanitis].
To describe the clinical and histopathological manifestations of a case of pseudoepitheliomatous, keratotic and micaceous balanitis and review the literature on this rare condition. A case of pseudoepitheliomatous, keratotic and micaceous balanitis in a 63-year-old man is presented. The lesion appeared a few months after undergoing circumcision due to phimosis and recurrent inflammatory balanitis. The lesion relapsed after topical treatment with 5-FU, cryotherapy and shaving-biopsy plus electrocoagulation. It was finally diagnosed as epidermoid carcinoma and surgically excised. The clinical and histopathological features, course and relationship between micaceous balanitis and carcinoma of the penis are reviewed.


Metal support effects in electrocatalysis at hexagonal boron nitride.
A scanning electrochemical droplet cell technique has been employed to screen the intrinsic electrocatalytic hydrogen evolution reaction (HER) activity of hexagonal boron nitride (h-BN) nanosheets supported on different metal substrates (Cu and Au). Local (spatially-resolved) voltammetry and Tafel analysis reveal that electronic interaction with the underlying metal substrate plays a significant role in modulating the electrocatalytic activity of h-BN, with Au-supported h-BN exhibiting significantly enhanced HER charge-transfer kinetics (exchange current is ca. two orders of magnitude larger) compared to Cu-supported h-BN, making the former material the superior support in a catalytic sense.


Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency.
Mice lacking the Gadd45a gene are susceptible to ionizing radiation-induced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10-14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45a-null mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV- and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.


Effects of social security policy reforms on mental health and inequalities: A systematic review of observational studies in high-income countries.
Evidence increasingly shows that changes to social security policies can affect population mental health. Thus, in the context of rising burden of mental illness, it is of major importance to better understand how expansions and contractions to the social security system may impact on mental health of both adults and children. The aim of this systematic review is to provide a synthesis of observational literature on the effects on mental health and inequalities in mental health of social security reforms. We conducted a systematic review of quantitative observational studies of specific national and regional social security policy changes in high-income countries and summarised the mental health effects of these policies. We searched seven electronic databases, including Medline, PsychInfo, Embase, CINAHL, ASSIA (Proquest), Scopus and Research Papers in Economics from January 1979 to June 2020. We included both objective and subjective mental health and wellbeing measures. The study quality was assessed using the Validity Assessment tool for econometric studies. We identified 13,403 original records, thirty-eight of which were included in the final review. Twenty-one studies evaluated expansionary social security policies and seventeen studies evaluated contractionary policies. Overall, we found that policies that improve social security benefit eligibility/generosity are associated with improvements in mental health, as reported by fourteen of the included studies. Social security policies that reduce eligibility/generosity were related to worse mental health, as reported by eleven studies. Ten studies found no effect for either policies contracting or expanding welfare support. Fourteen studies also evaluated the impact on mental health inequalities and found that contractionary policies tend to increase inequalities whereas expansionary policies have the opposite effect. Changes in social security policies can have significant effects on mental health and health inequalities across different recipient groups. Such health effects should be taken into account when designing future social policy reforms.


Genetic counselling in facioscapulohumeral muscular dystrophy.
Clinical data are presented from a survey of 41 families with dominantly inherited facioscapulohumeral muscular dystrophy (FSHD) in which over 500 family members were examined, including 168 affected subjects. New mutation could account for six isolated cases. Results suggest that 33% of heterozygotes over 40 years are mildly affected and a majority develop significant lower limb weakness; 19% over 40 years require wheelchairs. Presymptomatic testing of serum creatine kinase level (CK) is limited as a raised level occurs in only 80% of affected males under 40 years and 48% of affected women. Distribution of weakness, severity, age at onset, and CK varied between subjects, but provided no clinical evidence for genetic heterogeneity in a comparison between the 11 largest families. The conclusion of genetic homogeneity in FSHD, including subjects previously diagnosed as FSH type spinal muscular atrophy, is strongly supported by recent genetic linkage data.


Arterial hypertension following renal transplantation in children-a short-term study.
Systemic arterial hypertension is a common complication among transplanted patients. The objective of this study was to investigate the risk factors for arterial hypertension after kidney transplantation in children. A retrospective study was carried out of 70 kidney transplants performed on patients under 18 years of age at the Hospital do Rim and Hipertensão, from January 1998 to June 2001. At the end of 6 months post transplant, the patients were classified into either normotensive ( n=31) or hypertensive ( n=39) groups. The following potential risk factors for arterial hypertension were studied: (1) hypertension before transplantation; (2) the glomerular filtration rate (GFR) at 1, 3, and 6 months post transplant; (3) acute rejection episodes; (4) cumulative dose of corticosteroids; (5) the presence of native kidneys; (6) symptomatic renal artery stenosis; (7) cold ischemia time greater than 24 h; (8) age and sex of the donor; (9) age of the recipient; (10) transplant type (living related or cadaveric donor); (11) the body mass index of recipients at the end of the follow-up period; and (12) delayed graft function. The two groups were comparable in terms of the etiology of renal insufficiency, age, gender, and immunosuppressive drugs. Among the risk factors studied, the sole factor showing a statistically significant association with arterial hypertension was the GFR at 3 and 6 months after transplantation. In the group of normotensive patients, GFRs were 92+/-29 and 83+/-20 ml/min per 1.73 m(2) at 3 and 6 months, respectively, whereas in the hypertensive patients, GFRs were 74+/-23 and 70+/-21 ml/min per 1.73 m(2) respectively. Hence, only the lower GFR can be considered a risk factor for hypertension in children within our sample. However, arterial hypertension might be a risk factor for the early onset of chronic allograft nephropathy; in this case, hypertension should be considered the cause of lower glomerular filtration. Our data do not permit us to distinguish between these two hypotheses. The known risk factors for hypertension following renal transplantation in adults were not confirmed in the present study. It remains unclear to us as to whether this means the etiology of hypertension differs in children, or if this is the result of a bias in patient selection.


Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis.
Differentiating primary and secondary membranous glomerulonephritis (MGN) using biomarkers for MGN is essential in patients' diagnosis, treatment and follow-up. Although biopsy has been the primary tool in making the diagnosis, not all patients can withstand it due to its invasive nature, and it cannot be used to monitor treatment. Hence, there is the need for less invasive or even non-invasive biomarkers for effective diagnosis, treatment monitoring and prognostication. This study aimed at providing an alternative way of differentiating primary and secondary MGN using enzyme-linked immunosorbent assay (ELISA) technique for serum and urine biomarkers (M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A)) for prompt diagnosis, treatment and prognosis. A total of 125 subjects, including 81 primary and 44 secondary MGN subjects, were diagnosed from January 2012 to October 2019 at Hospital Serdang and Hospital Kuala Lumpur from which 69 subjects consisting of 45 primary and 24 secondary MGN subjects participated in the study. Of these, 13 primary MGN subjects were positive for both serum and urine anti-PLA2R antibodies (Ab) whereas only one secondary MGN subject associated with hepatitis B virus was positive for both serum and urine anti-PLA2R Ab. At the same time, anti-THSD7A Ab was found positive in four primary MGN subjects and two secondary MGN subjects with malignancy.


Modeling kinematics and dynamics of human arm movements.
A central problem in motor control relates to the coordination of the arm's many degrees of freedom. This problem concerns the many arm postures (kinematics) that correspond to the same hand position in space and the movement trajectories between begin and end position (dynamics) that result in the same arm postures. The aim of this study was to compare the predictions for arm kinematics by various models on human motor control with experimental data and to study the relation between kinematics and dynamics. Goal-directed arm movements were measured in 3-D space toward far and near targets. The results demonstrate that arm postures for a particular target depend on previous arm postures, contradicting Donders's law. The minimum-work and minimum-torque-change models, on the other hand, predict a much larger effect of initial posture than observed. These data suggest that both kinematics and dynamics affect postures and that their relative contribution might depend on instruction and task complexity.


The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. We examined the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. FFPE-tissue from the pancreatectomy of 145 patients was immunohistochemically stained for haematoxylin-eosin and Masson's trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). After a mean follow-up of 20 months (range, 2-69 months), the median OS was 21 months and the 3-year OS was 35.7%. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1-2) but not late (pT3-4) stage tumors. Additionally, late pT-stage (pT3-4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion and administration of adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Altogether, stroma density constitutes an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the dynamic complexity of desmoplasia and indicate that highly-dense stroma is correlated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC patients after adjuvant chemotherapy is warranted and will be performed in a prospective study.


The experimental induction of vitamin A deficiency in humans.
This is an historical account of experiments that were undertaken to determine the daily amount of vitamin A or carotene (or both) required for health of humans, by deliberately (and in one case accidentally) causing them to become vitamin A deficient. The recommended daily allowance determined by all of the experiments described arrived at roughly the same range, although large differences were reported for the time of appearance and the severity of observed signs and symptoms of the deficiency.


Imaging indexes of activity and severity for Crohn's disease: current status and future trends.
Cross-sectional imaging techniques, including ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) are increasingly used for evaluation of Crohn's disease (CD). To review the accuracy of cross-sectional imaging indexes for measurement of disease activity and severity in patients with CD, and to evaluate its applicability on daily clinical practice and research. Relevant publications were identified by literature search, and selected based on predefined quality parameters, including a sample size and reference standard. Nineteen publications were chosen. The US-based indexes of activity showed high correlation with reference standard indexes. There is a good or very good agreement between the MR-based indexes and the reference standard when the comparison is limited to small segments of intestine. Significant discrepancies have been found between indexes that evaluate the colon. Only one CT-based index was included. The main strengths and weaknesses of the indexes, according to its design, are discussed. Standardization of image acquisition protocols and patient preparation should be procured, especially for MRI. In daily practice, a simple, semi-quantitative index providing relevant information on disease activity and severity is preferable. For research purposes, a precise and reproducible index should be mandatory.


Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats.
Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs.Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal.Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels.Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine.Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels.


Installation and performance testing of an XtRa-NaI(Tl) Compton Suppression System at the NED-NTUA.
This paper presents the Compton Suppression System, recently installed at the Nuclear Engineering Department of NTUA. The system consists of an XtRa Ge detector coupled with a NaI(Tl) guard detector. The electronic set-up allows for the simultaneous collection of both the suppressed and the unsuppressed spectra. System performance is investigated using certified point and volume sources. Parameters such as Peak Suppression Factors, peak-to-Compton ratios and minimum detectable activity for specific radionuclides are determined.


Investigation of Viral Load Cycle Threshold Values in Patients with SARS-CoV-2 Associated Pneumonia with Real-Time PCR Method.
In this study, we aimed investigate the relationship of SARS-CoV-2 viral load cycle threshold (Ct) values with pneumonia. A total of 158 patients in whom SARS-CoV-2 was confirmed in upper respiratory tract (URT) samples with molecular method and who had computed tomography (CT) of the chest, between April 2020 and June 2020 were included in this retrospective cross-sectional study. Mean age of 158 PCR positive patients was 45.22 ± 17.89 and 60.8% of them were male. Pneumonia was detected in 40.5% of the patients on their chest CT. A weak but significant correlation was found between SARS-CoV-2 Ct value detected with PCR in analysis of oropharyngeal/ nasopharyngeal (OP/NP) samples and chest CT score (Pearson's r: 0.197, p = 0.01). No correlation was found between the first detected viral load Ct value and age, gender and mortality. There was no significant correlation between chest CT score and mortality. While the areas remaining under ROC curve for Ct value in analysis of OP/NP samples in prediction of chest CT score ≥ 1, ≥ 5 and ≥ 10 were 0.564, 0.640 and 0.703 respectively. We found that the amount of SARS-CoV-2 viral load (inverse relationship with Ct) detected in OP/NP samples of patients with COVID-19 pneumonia did not reflect the increasing severity of pulmonary lesions on chest CT. Although primary target of SARS-CoV-2 is all epithelial cells of the respiratory tract we believe studies comparing viral loads in lower respiratory tract samples are needed to determine the severity of pulmonary disease.


Identification of the constant chromosome regions involved in human hematologic malignant disease.
Specific consistent chromosome translocations are regularly observed in certain human leukemias and lymphomas. For the myeloid leukemias, the constant recombinants are: the long arm of 9 to chromosome 22 in chronic myeloid leukemia, the long arm of 21 to chromosome 8 in acute myeloblastic leukemia, and the long arm of 17 to chromosome 15 in acute promyelocytic leukemia. Three related translocations are seen in Burkitt lymphoma and B cell acute lymphocytic leukemia; in each one, chromosome 8 is involved with chromosome 2, 14, or 22. Analysis of a complex translocation affecting chromosomes 8 and 14 indicates that the translocation of chromosome 8 to chromosome 14 is the critical constant rearrangement. The analysis of the DNA at the translocation sites of these chromosomes, rather than the reciprocal of each translocation, appears to be the most productive focus for initial study. The various immunoglobulin loci are located in chromosomes 2, 14, and 22, the chromosomes regularly involved in translocations in Burkitt lymphoma and B cell acute lymphocytic leukemia.


Acute Reversible Renal Failure due to Glue Sniffing.
Glue sniffing refers to the deliberate inhalation of volatile solvents, commonly found in adhesives, for the purpose of intoxication. The globally increasing prevalence of glue sniffing suggests that physicians will encounter many such patients some time during their practice. We present a 19-year-old male who presented with acute abdomen and renal failure. He was treated conservatively and had complete recovery of renal functions in a week. The etiology of renal failure remained elusive on admission. While recovering from his illness, the patient revealed history of glue sniffing. The aim of presenting this case is to spread awareness among clinicians that glue sniffing should be considered in the differential diagnosis of unexplained acute reversible renal failure, particularly in young patients.


Alterations to the Gastrointestinal Microbiome Associated with Methamphetamine Use among Young Men who have Sex with Men.
Methamphetamine (MA) use is a major public health problem in the United States, especially among people living with HIV (PLWH). Many MA-induced neurotoxic effects are mediated by inflammation and gut microbiota may play a role in this process, yet the effects of MA on the microbiome have not been adequately explored. Therefore, we performed 16S rRNA gene sequencing on rectal swab samples from 381 men who have sex with men, 48% of whom were PLWH and 41% of whom used MA. We compared microbiome composition between MA users and non-users while testing for potential interactions with HIV and controlling for numerous confounders using inverse probability of treatment weighting. We found that MA use explained significant variation in overall composition (R2 = 0.005, p = 0.008) and was associated with elevated Finegoldia, Parvimonas, Peptoniphilus, and Porphyromonas and reduced Butyricicoccus and Faecalibacterium, among others. Genera including Actinomyces and Streptobacillus interacted with HIV status, such that they were increased in HIV+ MA users. Finegoldia and Peptoniphilus increased with increasing frequency of MA use, among others. In summary, MA use was associated with a microbial imbalance favoring pro-inflammatory bacteria, including some with neuroactive potential and others that have previously been associated with poor HIV outcomes.


Protocolised thromboelastometric-guided haemostatic management in patients with traumatic brain injury: a pilot study.
Coagulopathy in patients with traumatic brain injury is associated with an increase in morbidity and mortality. Although timely and aggressive treatment of coagulopathy is of paramount importance, excessive transfusion of blood products has been linked with poor long-term outcomes in patients with traumatic brain injury. A point-of-care thromboelastometric-guided algorithm could assist in creating a more individually tailored approach to each patient. The aim of this study was to evaluate the feasibility of implementing a thromboelastometric-guided algorithm in centres that were formerly naïve to thromboelastometry. Hence, we developed such an algorithm and provided training to four centres across Europe to direct the haemostatic management of patients with severe traumatic brain injury. The primary outcome was adherence to the algorithm and timing of the availability of relevant results. Thirty-two patients were included in the study. Complete adherence to the algorithm was observed in 20 out of 32 cases. The availability of thromboelastometric results after hospital admission was reported significantly earlier than conventional coagulation tests (median (IQR [range]) 33 (20-40 [14-250]) min vs. 71 (51-101 [32-290]) min; p = 0.037). Although only 5 out of 32 patients had abnormalities of conventional coagulation tests, 21 out of 32 patients had a coagulopathic baseline thromboelastometric trace. Implementing a thromboelastometric-guided algorithm for the haemostatic therapy of traumatic brain injury is feasible in centres formerly naïve to this technology and may lead to more rapid and precise coagulation management. Further large-scale studies are warranted to confirm the results of this pilot trial and evaluate clinical outcomes.


Epithelial ingrowth after Descemet-stripping automated endothelial keratoplasty.
To report the diagnosis and treatment of a patient who developed epithelial ingrowth after Descemet-stripping automated endothelial keratoplasty (DSAEK). We describe the case of an 80-year-old woman who underwent DSAEK for pseudophakic bullous keratopathy. After surgery, the patient underwent 2 additional rebubbling procedures for recurrent donor lenticule dislocation. She was subsequently found to have an enlarging interface epithelial ingrowth that led to graft failure. After donor lenticule exchange, mechanical scraping, and irrigation-aspiration of residual epithelial cells, there was no evidence of the histologically confirmed epithelial ingrowth during a 2-year follow-up interval. This 1 case report suggests that epithelial ingrowth may occur after DSAEK. This case was successfully treated surgically.


[Fatigue fractures of the calcaneus in soldiers of the Federal Forces].
Fatigue fractures of the calcaneus occur more frequently today than the typical march fractures of the metatarsal bones. The cause lies in the altered method of training with repeated jumping exercises and increased strain on the calcaneus. 203 fatigue fractures of the calcaneus were seen in 5 years, almost exclusively in recruits in the first 3 months of enlistment. 10 day after the beginning of pain in the calcaneus and swellings--in half of them bilateral-the X-ray showed typical zones of densification in the calcaneus. The treatment consists of decompression for 2 weeks until the complaint disappears.


Effects of 2',2'-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells.
2',2'-Difluorodeoxycytidine (Gemcitabine, dFdCyd) is a cytotoxic agent which is active toward a variety of tumor cells. It has been shown that there are multiple intracellular sites of action which include ribonucleotide reductase and DNA polymerase. In these studies, the effects of dFdCyd on wild-type mouse leukemia L1210 cells and variant L1210 cell lines which had alterations at the ribonucleotide reductase site or at the deoxyribonucleoside kinase site were studied. For cell growth, the IC50 value for dFdCyd in wild-type L1210 cells was 3.1 nM. In the variant cell lines, the IC50 values were: hydroxyurea-resistant (HU), 3.3 nM; deoxyadenosine-resistant (Y8), 1.8 nM; pyrazoloimidazole/deoxyadenosine-resistant (ED2), 1.9 nM; and deoxyguanosine-resistant (dGuo-R), 44.7 nM. The dGuo-R cell line had a relatively specific loss of the deoxyribonucleoside kinase responsible for phosphorylating deoxyguanosine and cytosine arabinoside with little loss of the deoxycytidine kinase activity. DFdCyd had no effect on the total uptake of [14C]cytidine into the cells or incorporation into RNA. DFdCyd inhibited the conversion of [14C]cytidine to deoxycytidine nucleotides and incorporation into DNA. However, the incorporation of cytidine into DNA was inhibited to a greater extent than was the inhibition of in situ ribonucleotide reductase activity. Ribonucleotide reductase activity in cell-free extracts prepared from L1210 cells treated with dFdCyd (20 nM) overnight was reduced by 50%. These results show that cell lines which have increased levels of ribonucleotide reductase activity (HU and ED2) or loss of feedback inhibition by dATP (ED2 and Y8) are still sensitive to dFdCyd. The findings indicate that ribonucleotide reductase is not the primary site of inhibition by dFdCyd.(ABSTRACT TRUNCATED AT 250 WORDS)


Wheat Coleoptile Inoculation by Fusarium graminearum for Large-scale Phenotypic Analysis.
The ascomycete fungus Fusarium graminearum is a destructive fungal pathogen of wheat, barley and maize. Although reverse genetics and homologous recombination gene deletion methods have generated thousands of gene deletion mutants of F. graminearum, evaluating virulence of these fungal mutants is still a rate-limiting step. Here we present a protocol for inoculation of wheat coleoptiles with conidial suspensions for large-scale phenotypic analysis, and describe how it can also be used to assess fungal infectious growth and symptom developmentat a cellular scale. The inoculation method described in this protocol provides highly reproducible results in wheat coleoptile infection by F. graminearum.


[Incidence and various risk factors for gout in the Georgian SSR].
The results of simultaneous epidemiological surveys of the adult population (7000 persons) in the city of Tbilisi and workers at 7 enterprises of the machine-building and mining industries (9189) have shown that 0.29% of the population, mainly men aged over 40 with hereditary predisposition, obesity, carbohydrate metabolic derangement, consuming food rich in purine bases, national flavorings and spices, suffer from gout. A high prevalence of gout among workers of the mining industry and early age at the onset of disease suggest probable association of gout with some industrial factors (manganese, tungsten, molybdenum, bismuth).


Environmental, psychological, and social influences on physical activity among Japanese adults: structural equation modeling analysis.
An understanding of the contributing factors to be considered when examining how individuals engage in physical activity is important for promoting population-based physical activity. The environment influences long-term effects on population-based health behaviors. Personal variables, such as self-efficacy and social support, can act as mediators of the predictive relationship between the environment and physical activity. The present study examines the direct and indirect effects of environmental, psychological, and social factors on walking, moderate-intensity activity excluding walking, and vigorous-intensity activity among Japanese adults. The participants included 1,928 Japanese adults aged 20-79 years. Seven sociodemographic attributes (e.g., gender, age, education level, employment status), psychological variables (self-efficacy, pros, and cons), social variables (social support), environmental variables (home fitness equipment, access to facilities, neighborhood safety, aesthetic sensibilities, and frequency of observing others exercising), and the International Physical Activity Questionnaire were assessed via an Internet-based survey. Structural equation modeling was conducted to determine associations between environmental, psychological, and social factors with physical activity. Environmental factors could be seen to have indirect effects on physical activity through their influence on psychological and social variables such as self-efficacy, pros and cons, and social support. The strongest indirect effects could be observed by examining the consequences of environmental factors on physical activity through cons to self-efficacy. The total effects of environmental factors on physical activity were 0.02 on walking, 0.02 on moderate-intensity activity excluding walking, and 0.05 on vigorous-intensity activity. The present study indicates that environmental factors had indirect effects on walking, moderate-intensity activity excluding walking and vigorous-intensity activity among Japanese adults, especially through the effects on these factors of self-efficacy, social support, and pros and cons. The findings of the present study imply that intervention strategies to promote more engagement in physical activity for population-based health promotion may be necessary.


Control of translation elongation in health and disease.
Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.


Is fibreoptic percutaneous tracheostomy in ICU a breakthrough.
In ICUs, bedside percutaneous tracheostomy (pct) is commonly performed, but it is associated with certain drawbacks as paratracheal placement, posterior tracheal wall injury and tracheoesophageal fistula. To address these fibreoptic bronchoscope (FOB) guided PCT was introduced. We aimed to compare both these methods. PATIENTS #ENTITYSTARTX00026; We compared 60 age & sex matched patients into two groups of 30 each. In group 1 tracheostomy was performed by the conventional Ciaglia's method. In group 2, a fibreoptic bronchoscope was used in addition with the aid of an assistant. The fiberoptic method took more time than the conventional method. (18±3min vs 15±2min (p=0.001)). The average no. of attempts at insertion of needle was 2.4 in group 1 and 1.2 in group 2 (p=0.001). The fall in SpO2 to <90% was seen in 1 patient in group 1 and in 6 patients in group 2, so much so that the procedure had to be abandoned in 2 patients. FOB though definitely advantageous over CPCT in terms of lesser complications and being highly useful in the obese, short necked, and those with scar marks, is not without drawbacks such as requirement of additional staff and increased expenditure. The main being inability to be used in patients with low respiratory reserve. Overall it would be complimentary for any ICU to have FOB facility and must be used in select group of patients.


B Lymphoblastic Leukemia/Lymphoma With Burkitt-like Morphology and IGH/MYC Rearrangement: Report of 3 Cases in Adult Patients.
Isolated MYC rearrangement without other recurrent genetic abnormalities is rare in B lymphoblastic leukemia/lymphoma (B-ALL/LBL), with most cases reported in pediatric patients. We report 3 adult cases with lymphoblasts showing a precursor B cell immunophenotype, and isolated MYC/IGH translocation. All 3 cases occurred in male patients with initial presentation of diffuse lymphadenopathy. Cases 1 and 2 had B-ALL with significantly increased lymphoblasts in peripheral blood and bone marrow. Case 3, a patient with human immunodeficiency virus infection, had the diagnosis of B-LBL made on a retroperitoneal lymph node biopsy and had no peripheral blood or bone marrow involvement. The leukemic and lymphoma cells in all 3 cases demonstrated Burkitt lymphoma-like morphology with deeply basophilic cytoplasm and numerous cytoplasmic vacuoles. However, all 3 had immature immunophenotypes including expression of terminal deoxynucleotidyl transferase (TdT), absence of BCL6, and dim-to-negative CD45. CD20 was largely negative in 2 of 3 cases. All 3 had confirmed MYC/IGH translocation, but lacked rearrangements of BCL2 or BCL6. EBV was negative by Epstein-Barr virus encoded small RNA in situ hybridization. Treatment protocols varied, including both high-risk ALL-type (protocol 8707) and high-grade lymphoma regimens (hyper-CVAD [cyclophosphamide, vincristine, adriamycin, and dexamethasone]), but no patient achieved continuous complete remission. These cases seem to represent a distinct biological phenomenon, in which a MYC translocation may be acquired at an immature stage of differentiation, thus manifesting features of both B-ALL/LBL and Burkitt lymphoma.


Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity.
Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.


Accrued Cost Savings of a Free Clinic Using Quality-Adjusted Life Years Saved and Return on Investment.
Savings garnered through the provision of preventive services is a form of profit for health systems. Free clinics have been using this logic to demonstrate their cost-savings. The Community-Based Chronic Disease Management (CCDM) clinic treats hypertension using nurse-led teams, clinical protocols, and community-based settings. We calculated CCDM's cost-effectiveness from 2007 to 2013 using 2 metrics: Quality-adjusted life years (QALYs) saved and return on investment (ROI). QALYs were calculated using the Clinical Preventive Burden (CPB) score for hypertension care. ROI was calculated by tallying the savings from prevented heart attacks, strokes, and emergency department visits against the total operating costs. Using conservative assumptions for cost estimates, hypertension care resulted in a value of QALYs saved of $711,000 to $2,133,000 and an ROI ratio range of 0.35 to 1.20. Our study shows that when using conservative assumptions to calculate cost-savings, our free clinic did not save money. Cost-savings did occur, but the amount was modest, was less than that of cost-inputs, and was not likely captured by any single health entity. Although free clinics remain a vital health care access point for many Americans, it has yet to be demonstrated that they generate a net savings.


[Possibilities of pacing the heart by transmediastinal retrocardially inserted leads (author's transl)].
Based upon experiences with 14 patients the clinical feasibility of transmediastinal retrocardial stimulation of the heart, of the left atrium as well as in one case of the left ventricle, is reported. Principally both can be stimulated by thus introduced pacemaker electodes. Thus on the one hand thresholds and consequently pulse effectivity appear to be a function of the electrode distance from the myocardium, whilst on the other hand the transmediastinal retrocardial thresholds are initially rather high in analogy to the majority taken from the atrial endocardial surface. Nevertheless, the transmediastinal retrocardial technique is possibly applicable for permanent cardiac pacing. However, additional tests about this are still necessary.


An increase in cellular size variance contributes to the increase in ultrasound backscatter during cell death.
This study aims to explain the contribution of changes in cellular size variance (CSV) to increases in ultrasound-integrated backscatter (UIB) measured from cell samples undergoing cell death. A Monte Carlo algorithm was used to compare simulations of 2D distributions of cells, uniform (CSV = 0) versus heterogeneous (CSV > 0) and the same mean cellular size (M ). UIB increased in arrangements with heterogeneous cellular sizes from 3.6dB (M = 20 mum, CSV = 0 microm/CSV = 18 microm) to 5.6 dB (M =10 microm, CSV = 0 microm/CSV = 8 microm). Experimentally, UIB (10 to 30 MHz) was measured from cell samples of four tumor cell lines viable and undergoing cell death after radiotherapy and chemotherapy treatment. An increase of 3.8-7.5 dB (p < 0.001) in UIB was measured from three cell lines. No increase in UIB was measured from one cell line. An increase in CSV was found for all cell samples after cell death. The results suggest that an increase in CSV could have a significant contribution to the increases measured in UIB after cell death in cell samples exposed to anticancer therapies.


[Term birth of a twin after the rupture of the uterine horn at 15 weeks gestational age].
Having treated a case which resulted in the delivery at term of an intrauterine twin when the other twin had been lost after the rupture of a uterine cornu which itself followed a salpingectomy without removal of the interstitial portion of the tube brings the authors to discuss the physiopathology and the symptomatology of such cases. They also discuss the value of resecting the interstitial portion of the tube and what management should be when there is a live intrauterine pregnancy.


[Two stages in the digestion of proteins by pepsin].
Studies on a monosubstrate system (pepsin - substrate) yielded values which characterize pepsin digestion as a multi-stage process. During the first stage, pepsin hydrolyzes the most accessible parts of the protein molecule, i.e., those portions of the peptide chains which are situated on the surface of the globule. During the stage of apparent cessation of the reaction, very few peptide bonds are hydrolyzed which are essential for the formation of the tertiary structure. After hydrolysis of these bonds, the inner parts of the globule become accessible, the hydrolysis of which proceeds more slowly.


A brief 5-item version of the Neck Disability Index shows good psychometric properties.
The purpose of this secondary analysis of clinical databases of people with neck pain was to use a mixed unique conceptual and statistical approach to develop a brief version of the Neck Disability Index (NDI). An a priori framework of neck-related function based on the International Classification of Functioning, Disability and Health was used to identify items from the original 10-item NDI that do not conceptually fit. Remaining items were subject to Rasch analysis to identify items that did not statistically fit with axioms of quantitative measurement. Finally, approaches drawn from classical test theory were used to compare stability, responsiveness and concurrent validity of the original NDI, the new brief NDI and the linearly-transformed brief NDI. Conceptual analysis identified 3 items that did not fit with the construct of self-reported ability to perform activity: pain intensity, headache, and sleeping. These items were removed, and responses to the remaining 7 items drawn from an assembled database of 316 physiotherapy patients with neck pain were subject to Rasch analysis. Two items were removed due to either considerable differential item functioning (reading) or statistical redundancy (lifting). The remaining items were considered the NDI-5. Test-retest reliability, responsiveness, sensitivity to change, and concurrent validity were all comparable across the original NDI, NDI-5 and linearly-transformed NDI-5. Sensitivity to change over a 1-month period of physiotherapy was the notable exception, where the linearly-transformed NDI-5 showed superiority over the other two forms. A shortened version of the NDI, the NDI-5, has been constructed that is conceptually and statistically sound. Implications for research and clinical practice are discussed. Comparison with the NDI-8 is provided that suggests overall similar function across the forms, although the latter may be more sensitive to change.


Shared decision-making approach to taper postoperative opioids in spine surgery patients with preoperative opioid use: a randomized controlled trial.
Persistent opioid use is common after surgery, and patients with preoperative opioid use represent a major challenge in this regard. The aim of this randomized controlled trial was to determine the effect of a personalized opioid tapering plan vs standard of care in patients with a preoperative opioid use undergoing spine surgery at Aarhus University Hospital, Denmark. Postoperative outcomes included opioid use, pain, contacts with the healthcare system, patient satisfaction, and withdrawal symptoms. Overall, 110 patients were randomized; 55 into the intervention and control groups each. Five patients (proportion = 0.09, 95% confidence interval [CI] [0.04-0.21]) in the intervention group compared with 13 patients (0.25, 95% CI [0.15-0.39]) in the control group were unable to taper opioids to their preoperative consumption 1 month after discharge (P = 0.03) (primary outcome). Likewise, more patients in the intervention group succeeded in tapering opioids to zero 3 months after discharge (37 patients; 0.71, 95% CI [0.57-0.82] vs 23 patients; 0.43, 95% CI [0.30-0.56], P = 0.003). Fewer patients in the intervention group had pain-related contacts to health care the first 2 weeks after discharge (21 patients; 0.40, 95% CI [0.28-0.54] vs 31 patients; 0.60, 95% CI [0.46-0.73], P = 0.04). There was no difference in satisfaction with pain treatment over the first 2 weeks or the incidence of withdrawal symptoms during the first month after discharge. Pain intensity was similar between both groups at all time points. These results suggest that a personalized tapering plan at discharge combined with telephone counselling 1 week after discharge assists patients in postoperative opioid tapering.


Human beta 2-adrenergic receptors expressed in Escherichia coli membranes retain their pharmacological properties.
The coding region of the gene for the human beta 2-adrenergic receptor gene was fused to the beta-galactosidase gene of the lambda gt11 expression vector. The Y1089 Escherichia coli strain was lysogenized with this modified vector and transcription of the fusion gene was induced. Expression of this transcription unit was shown by the appearance in the bacteria of proteins of molecular weight higher than that of native beta-galactosidase, which are immunoreactive with anti-beta-galactosidase antibodies. Production of beta 2-adrenergic receptors was shown by the presence, on intact bacteria, of binding sites for catecholamine agonists and antagonists possessing a typical beta 2-adrenergic pharmacological profile. Binding and photoaffinity labeling studies performed on intact E. coli and its membrane fractions showed that these binding sites are located in the inner membrane of the bacteria. Expression of pharmacologically active human beta 2-adrenergic receptors in E. coli further supports the similar transmembrane organization proposed for bacteriorhodopsin and eukaryotic membrane-embedded receptors coupled to guanine nucleotide-binding regulatory proteins. Moreover, this system should facilitate future analyses of the ligand-binding properties within this family of membrane receptors.


Lexical processing in deaf readers: an FMRI investigation of reading proficiency.
Individuals with significant hearing loss often fail to attain competency in reading orthographic scripts which encode the sound properties of spoken language. Nevertheless, some profoundly deaf individuals do learn to read at age-appropriate levels. The question of what differentiates proficient deaf readers from less-proficient readers is poorly understood but topical, as efforts to develop appropriate and effective interventions are needed. This study uses functional magnetic resonance imaging (fMRI) to examine brain activation in deaf readers (N = 21), comparing proficient (N = 11) and less proficient (N = 10) readers' performance in a widely used test of implicit reading. Proficient deaf readers activated left inferior frontal gyrus and left middle and superior temporal gyrus in a pattern that is consistent with regions reported in hearing readers. In contrast, the less-proficient readers exhibited a pattern of response characterized by inferior and middle frontal lobe activation (right>left) which bears some similarity to areas reported in studies of logographic reading, raising the possibility that these individuals are using a qualitatively different mode of orthographic processing than is traditionally observed in hearing individuals reading sound-based scripts. The evaluation of proficient and less-proficient readers points to different modes of processing printed English words. Importantly, these preliminary findings allow us to begin to establish the impact of linguistic and educational factors on the neural systems that underlie reading achievement in profoundly deaf individuals.


Understanding inflammatory pain: ion channels contributing to acute and chronic nociception.
Inflammatory pain results from the increased excitability of peripheral nociceptive sensory fibres produced by the action of inflammatory mediators. This excitatory effect, in turn, is a result of the altered activity of ion channels within affected sensory fibres. This review will consider the molecular consequences of inflammation within the peripheral nerves with particular focus on the effects of different inflammatory mediators on the ion channels in sensory neurons. We will discuss the main signalling pathways triggered in neurons by inflammatory mediators; the ionic mechanisms underlying inflammatory hyperalgesia and spontaneous inflammatory pain and finally will briefly consider ion channels underlying pain in chronic inflammation.


Effectiveness of facility-based personalized maternal nutrition counseling in improving child growth and morbidity up to 18 months: A cluster-randomized controlled trial in rural Burkina Faso.
The period from conception to 24 months of age is a crucial window for nutrition interventions. Personalized maternal counseling may improve childbirth outcomes, growth, and health. We assessed the effectiveness of facility-based personalized maternal nutrition counseling (from pregnancy to 18 months after birth) in improving child growth and health in rural Burkina Faso. We conducted a paired cluster randomized controlled trial in a rural district of Burkina Faso with 12 primary health centers (clusters). Healthcare providers in the intervention centers received patient-centered communication and nutrition counseling training. Pregnant women in the third trimester living in the center catchment areas and intending to stay for the next 2 years were prospectively included. We followed 2253 mother-child pairs quarterly until the child was aged 18 months. Women were interviewed about counseling experiences, dietary practices during pregnancy, and their child's feeding practices and morbidity history. Anthropometric measurements were taken at each visit using standardized methods. The primary outcomes were the cumulative incidence of wasting, and changes in child weight-for-height z-score (WHZ). Secondary outcomes were the women's prenatal dietary practices, early breastfeeding practices, exclusive breastfeeding, timely introduction of complementary food, child's feeding frequency and dietary diversity, children's mean birth weight, endpoint prevalence of stunting, and cumulative incidence of diarrhea, fever, and acute respiratory infection. All analyses were by intention-to-treat using mixed effects models. The intervention and control arms each included six health centers. Mothers in the intervention arm had a significantly higher exposure to counseling with 11.2% for breastfeeding techniques to 75.7% for counseling on exclusive breastfeeding. Mothers of infants below 6 months of age in the intervention arm were more likely to exclusively breastfeed (54.3% vs 42.3%; Difference of Proportion (DP) 12.8%; 95% CI: 2.1, 23.6; p = 0.020) as compared to the control arm. Between 6 and 18 months of age, more children in the intervention arm benefited from the required feeding frequency (68.8% vs 53.4%; DP 14.1%; 95% CI: 9.0, 19.2; p<0.001) and a larger proportion had a minimum dietary diversity (28.6% vs 22.0%; DP 5.9%; 95% CI: 2.7, 9.2; p<0.001). Birth weight of newborns in the intervention arm was on average 84.8 g (p = 0.037) larger compared to the control arm. However, we found no significant differences in child anthropometry or morbidity between study arms. Facility-based personalized maternal nutrition counseling was associated with an improved prenatal dietary practices, Infant and Young Child Feeding practices, and child birth weight. Complementary strategies are warranted to obtain meaningful impact on child growth and morbidity. This includes strategies to ensure good coverage of facility-based services and effective nutrition/care practices in early childhood.


Advanced Non-Destructive Ocular Visualization Methods by Improved X-Ray Imaging Techniques.
Due to limited X-ray contrast, the use of micro-CT in histology is so far not as widespread as predicted. While specific staining procedures-mostly using iodine-address this shortcoming, long diffusion times restrict its use in the often time-constrained daily routine. Recently, a novel staining protocol has been proposed using a biochemical preconditioning step, which increases the permeability of the cells for the staining agent. This could enable the imaging of entire organs of small mammals at a yet unmatched image quality with reasonable preparation and scan times. We here propose an adaptation of this technique for virtual ophthalmology and histology by volumetrically assessing both human and porcine eyes. Hereby, we demonstrate that (contrast-enhanced) micro-CT can outperform conventional histology in the assessment of tumor entities, as well as functioning as a supplementary tool for surgeons in the positioning of intraocular implants in-vitro and as a general assessment tool for ophthalmologic specimens.


Unraveling the distribution characteristic of cyclic volatile methylsiloxanes in various environmental media of a wastewater treatment plant.
Cyclic volatile methylsiloxane (cVMS) is extensively used in consumer products and frequently detected in various environmental media, including water and air. In this study, we developed reliable and convenient methods to sample three cVMS compounds: octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) in water and air samples collected from different tanks within a wastewater treatment plant (WWTP). The concentrations of D4, D5, and D6 in the water samples ranged from 0.40 to 8.0 μg L-1, 0.35 to 91 μg L-1, and 0.54 to 17 μg L-1, respectively. In the air samples, these concentrations varied from 0.34 to 20 μg m-3, 0.34 to 128 μg m-3, and 0.08 to 12 μg m-3, respectively. It is worth noting that the air-water distribution coefficient (Kaw) for these three cVMS exhibited a strong correlation with their water solubility. Moreover, fugacity fractions indicated a net evaporation process from water to the atmosphere. Furthermore, we investigated the distribution of cVMS between the gaseous and particulate phases. The results revealed a significant fraction, exceeding 72 %, of cVMS resided in the gas phase. D4 and D5 predominate in the gaseous phase, while D5 and D6 are the principal constituents within the particulate phase. The distribution coefficient characterizing the partitioning of cVMS compounds between the gaseous and particulate (Kp) exhibited a strong correlation with their corresponding octanol-air partitioning coefficients (Koa). These findings contribute to a better understanding of the distribution of cVMS in diverse environmental media and the underlying mechanism governing their dispersion.


Preliminary characterization of coxsackievirus B3 temperature-sensitive mutants.
Prototype temperature-sensitive (ts) mutants of a coxsackievirus B3 parent virus capable of replication to similar levels at 34 or 39.5 degrees C were examined for the nature of the temperature-sensitive event restricting replication in HeLa cells at 39.5 degrees C. The ts mutant prototypes represented three different non-overlapping complementation groups. The ts1 mutant (complementation group III) synthesized less than 1% of the infectious genomic RNA synthesized by the coxsackievirus B3 parent virus at 39.5 degrees C and was designated an RNA- mutant. Agarose gel analysis of glyoxal-treated RNA from cells inoculated with ts1 virus revealed that cell RNA synthesis continued in the presence of synthesis of the small amount of viral RNA. This mutant was comparatively ineffective in inducing cell cytopathology and in directing synthesis of viral polypeptides, likely due to the paucity of nascent genomes for translation. The ts5 mutant (complementation group II) directed synthesis of appreciable quantities of both viral genomes (RNA+) and capsid polypeptides; however, assembly of these products into virions occurred at a low frequency, and virions assembled at 39.5 degrees C were highly unstable at that temperature. Shift-down experiments with ts5-inoculated cells showed that capsid precursor materials synthesized at 39.5 degrees C can, after shift to 34 degrees C, be incorporated into ts5 virions. We suggest that the temperature-sensitive defect in this prototype is in the synthesis of one of the capsid polypeptides that cannot renature into the correct configuration required for stability in the capsid at 39.5 degrees C. The ts11 mutant (complementation group I) also synthesized appreciable amounts of viral genomes (RNA+) and viral polypeptides at 39.5 degrees C. Assembly of ts11 virions at 39.5 degrees C occurred at a low frequency, and the stability of these virions at 39.5 degrees C was similar to that of the parent coxsackievirus B3 virions. The temperature-sensitive defect in the ts11 prototype is apparently in assembly. The differences in biochemical properties of the three prototype ts mutants at temperatures above 34 degrees C may ultimately offer insight into the differences in pathogenicity observed in neonatal mice for the three prototype ts mutants.


Nonneoplastic endometrial signet-ring cells. Vacuolated decidual cells and stromal histiocytes mimicking adenocarcinoma.
We describe 5 patients (mean age, 50 years; all had uterine bleeding) whose routine endometrial biopsy and curettage specimens contained prominent signet-ring cells. Each specimen contained loose aggregates of signet-ring cells scattered within the endometrial stroma that were characterized by peripherally displaced, small, uniform nuclei with indistinct nucleoli and showed no mitotic activity. The central portion of the cytoplasm was occupied by single or multiple cytoplasmic vacuoles. In all cases, the signet-ring cells were reactive for vimentin and negative for epithelial membrane antigen and cytokeratin. Four cases were focally positive for muscle-specific actin or smooth muscle actin and negative for CD68, Mac387, periodic acid-Schiff, mucicarmine, and alcian blue. In these 4 cases, the surrounding endometrial stroma showed decidual changes, and the signet-ring cells demonstrated a morphologic continuum with more typical decidualized stroma. As such, the signet-ring cells in these cases were vacuolated, decidualized endometrial stromal cells. In the remaining case, the vacuolar contents of the signet-ring cells were periodic acid-Schiff-positive and resistant to diastase predigestion, and the cells reacted with Mac387 and CD68. The surrounding stroma showed no decidual reaction. Thus, the signet-ring cells in this case were of histiocytic differentiation. Endometrial stroma occasionally may contain nonneoplastic signet-ring cells that closely mimic adenocarcinoma. At least 2 directions of differentiation, decidual and histiocytic, are possible.


Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.
Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre-established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated. Here, we address if CLA primes monocytes towards an anti-inflammatory MΦ2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation, cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages. cis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARγ and LXRα dependent pathways. The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.


Semantic Extraction of Permanent Structures for the Reconstruction of Building Interiors from Point Clouds.
The extraction of permanent structures (such as walls, floors, and ceilings) is an important step in the reconstruction of building interiors from point clouds. These permanent structures are, in general, assumed to be planar. However, point clouds from building interiors often also contain clutter with planar surfaces such as furniture, cabinets, etc. Hence, not all planar surfaces that are extracted belong to permanent structures. This is undesirable as it can result in geometric errors in the reconstruction. Therefore, it is important that reconstruction methods can correctly detect and extract all permanent structures even in the presence of such clutter. We propose to perform semantic scene completion using deep learning, prior to the extraction of permanent structures to improve the reconstruction results. For this, we started from the ScanComplete network proposed by Dai et al. We adapted the network to use a different input representation to eliminate the need for scanning trajectory information as this is not always available. Furthermore, we optimized the architecture to make inference and training significantly faster. To further improve the results of the network, we created a more realistic dataset based on real-life scans from building interiors. The experimental results show that our approach significantly improves the extraction of the permanent structures from both synthetically generated as well as real-life point clouds, thereby improving the overall reconstruction results.


A critical appraisal of guidelines used for management of severe acute malnutrition in South Africa's referral system.
Focusing on healthcare referral processes for children with severe acute malnutrition (SAM) in South Africa, this paper discusses the comprehensiveness of documents (global and national) that guide the country's SAM healthcare. This research is relevant because South African studies on SAM mostly examine the implementation of WHO guidelines in hospitals, making their technical relevance to the country's lower level and referral healthcare system under-explored. To add to both literature and methods for studying SAM healthcare, we critically appraised four child healthcare guidelines (global and national) and conducted complementary expert interviews (n = 5). Combining both methods enabled us to examine the comprehensiveness of the documents as related to guiding SAM healthcare within the country's referral system as well as the credibility (rigour and stakeholder representation) of the guideline documents' development process. None of the guidelines appraised covered all steps of SAM referrals; however, each addressed certain steps thoroughly, apart from transit care. Our study also revealed that national documents were mostly modelled after WHO guidelines but were not explicitly adapted to local context. Furthermore, we found most guidelines' formulation processes to be unclear and stakeholder involvement in the process to be minimal. In adapting guidelines for management of SAM in South Africa, it is important that local context applicability is taken into consideration. In doing this, wider stakeholder involvement is essential; this is important because factors that affect SAM management go beyond in-hospital care. Community, civil society, medical and administrative involvement during guideline formulation processes will enhance acceptability and adherence to the guidelines.


Measurement of roughness based on the Talbot effect in reflection from rough surfaces.
In the present work, the Talbot effect of a square grating is analyzed when light is reflected from a rough surface. It is shown theoretically that the scattered light intensity in the Fresnel diffraction limit depends on statistical properties of the rough surface, the angle of incidence of the light, the grating period, and a geometric coefficient, related to the ratio of distance of the rough surface and the observation plane from the grating. At Talbot distances of the grating, the surface height difference function, in terms of multiplication of the Talbot number, the grating period, and the geometric coefficient is the modulation transfer function (MTF) of the scattering in reflection from the rough surface. If the argument of the height difference function is larger than twice the surface correlation length, the height difference function is constant for different spatial frequencies. Therefore, the square wave is reproduced with smaller contrast. The surface roughness can be obtained by measuring the contrast at different incident angles. It is also shown that the contrast measurements in both reflection and transmission, provide the refractive index of transparent samples with a rough surface. In experimental studies, the roughness of three metal standard rough surfaces are determined at different angles of incidence. Also, the refractive index of a sheet glass with a rough surface is obtained. The results are quite consistent.


Mirror-based flexible one-step calibration method of light-sectioning system for surface topography.
A flexible, easy-to-implement, one-step calibration method of the light-sectioning system is proposed for surface topography using a mirror adapter. The calibration method employs an arbitrary non-planar object with feature points as a target. With the assistance of the mirror adapter, the real and the reflected images of calibration are spatially separated and captured by a camera. It is developed as a direct calculation (DC) method and a virtual camera (VC) method to optimize the full parameters of the system. The DC method estimates the relative rotation and translation, respectively, and the VC method regards the two images as captured by two cameras in a physical sense through image flipping. The parameters of the laser plane can be solved accordingly. A numerical simulation is performed to analyze the precision of these two methods. A three-dimensional (3D) toy and a mechanical element are measured to verify the validity in translation experiments.


Exposure to aflatoxin B1 in utero is associated with DNA methylation in white blood cells of infants in The Gambia.
Exposure to environmental toxins during embryonic development may lead to epigenetic changes that influence disease risk in later life. Aflatoxin is a contaminant of staple foods in sub-Saharan Africa, is a known human liver carcinogen and has been associated with stunting in infants. We have measured aflatoxin exposure in 115 pregnant women in The Gambia and examined the DNA methylation status of white blood cells from their infants at 2-8 months old (mean 3.6 ± 0.9). Aflatoxin exposure in women was assessed using an ELISA method to measure aflatoxin albumin (AF-alb) adducts in plasma taken at 1-16 weeks of pregnancy. Genome-wide DNA methylation of infant white blood cells was measured using the Illumina Infinium HumanMethylation450beadchip. AF-alb levels ranged from 3.9 to 458.4 pg/mg albumin. We found that aflatoxin exposure in the mothers was associated to DNA methylation in their infants for 71 CpG sites (false discovery rate < 0.05), with an average effect size of 1.7% change in methylation. Aflatoxin-associated differential methylation was observed in growth factor genes such as FGF12 and IGF1, and immune-related genes such as CCL28, TLR2 and TGFBI. Moreover, one aflatoxin-associated methylation region (corresponding to the miR-4520b locus) was identified. This study shows that maternal exposure to aflatoxin during the early stages of pregnancy is associated with differential DNA methylation patterns of infants, including in genes related to growth and immune function. This reinforces the need for interventions to reduce aflatoxin exposure, especially during critical periods of fetal and infant development.


Twelve Tips for Synergistic Delivery of Remote Advanced Pharmacy Practice Experience Rotations.
This article was migrated. The article was marked as recommended. In response to the COVID-19 pandemic, many institutions changed their staffing models to incorporate remote work which created a need for pharmacy faculty and preceptors to also shift their rotation experience to a remote format. While initially this may be a daunting task, remote experiences have the potential to equip students with unique skillsets while offering a mutually beneficial effort towards patient care and/or other responsibilities. In addition, these remote experiences can offer students a more customized rotation and a behind the scenes look at the preceptor's career. This article provides 12 tips for developing a remote learning experience.


Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.
Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012. To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases. For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review. We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis. We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.


A brief intervention for weight management in primary care: study protocol for a randomized controlled trial.
Obesity affects 25% of the UK adult population but modest weight loss can reduce the incidence of obesity-related chronic disease. Some effective weight loss treatments exist but there is no nationally available National Health Service (NHS) treatment service, and general practitioners (GPs) rarely discuss weight management with patients or support behavior change. Evidence shows that commercial weight management services, that most primary care trusts have 'on prescription', are more effective than primary care treatment. We propose a controlled trial where patients will be randomized to receive either the offer of help by referral to a weight management service and follow-up to assess progress, or advice to lose weight on medical grounds. The primary outcome will be weight change at 12-months. Other questions are: what actions do people take to manage their weight in response to the two GP intervention types? How do obese patients feel about GPs opportunistically discussing weight management and how does this vary by intervention type? How do GPs feel about raising the issue opportunistically and giving the two types of brief intervention? What is the cost per kg/m2 lost for each intervention? Research assistants visiting GP practices in England (n = 60) would objectively measure weight and height prior to GP consultations and randomize willing patients (body mass index 30+, excess body fat, 18+ years) using sealed envelopes. Full recruitment (n = 1824) is feasible in 46 weeks, requiring six sessions of advice-giving per GP. Participants will be contacted at 3 months (postintervention) via telephone to identify actions they have taken to manage their weight. We will book appointments for participants to be seen at their GP practice for a 12-month follow-up. Trial results could make the case for brief interventions for obese people consulting their GP and introduce widespread simple treatments akin to the NHS Stop Smoking Service. Likewise, the intervention could be introduced in the Quality and Outcomes Framework and influence practice worldwide. Current Controlled Trials ISRCTN26563137.


Long-term outcome of pomalidomide therapy in myelofibrosis.
Ninety-four Mayo Clinic patients with myelofibrosis (MF) participated in two consecutive clinical trials of pomalidomide (0.5-3.5 mg/day), with or without prednisone. Overall anemia response was 27% and increased to 53% in JAK2V617F-positive patients with <10 cm palpable splenomegaly and <5% circulating blasts; response rate was 0% in mutation-negative patients with either ≥10 cm splenomegaly or ≥5% circulating blasts (P = 0.0001). Median duration of anemia response was 16 months. Treatment effect on splenomegaly was negligible. To date, pomalidomide therapy has been discontinued in 86 (91%) patients at a rate of 68% at 1 year and 89% at 2 years. Grade 1 sensory neuropathy developed in 4 (13%) of 30 patients treated for ≥1 year. Risk-adjusted survival in pomalidomide-treated primary MF patients (n = 72) was similar to their counterparts not exposed to the drug (n = 471; P = 0.19). Long-term follow-up of pomalidomide treatment in MF reveals palliative value for a select group of patients and treatment-emergent sensory neuropathy.


On the design of broad based screening assays to identify potential pharmacological chaperones of protein misfolding diseases.
Correcting aberrant folds that develop during protein folding disease states is now an active research endeavor that is attracting increasing attention from both academic and industrial circles. One particular approach focuses on developing or identifying small molecule correctors or pharmacological chaperones that specifically stabilize the native fold. Unfortunately, the limited screening platforms available to rapidly identify or validate potential drug candidates are usually inadequate or slow because the folding disease proteins in question are often transiently folded and/or aggregation-prone, complicating and/or interfering with the assay outcomes. In this review, we outline and discuss the numerous platform options currently being employed to identify small molecule therapeutics for folding diseases. Finally, we describe a new stability screening approach that is broad based and is easily applicable toward a very large number of both common and rare protein folding diseases. The label free screening method described herein couples the promiscuity of the GroEL binding to transient aggregation-prone hydrophobic folds with surface plasmon resonance enabling one to rapidly identify potential small molecule pharmacological chaperones.


Development of Persistent Opioid Use After Cardiac Surgery.
The overuse of opioids for acute pain management has led to an epidemic of persistent opioid use. To determine the proportion of opioid-naive patients who develop persistent opioid use after cardiac surgery and investigate the association between the initial amount of opioids prescribed at discharge and the likelihood of developing new persistent opioid use. This retrospective cohort study used data from a national administrative claims database from January 1, 2004, to December 31, 2016 and included 35 817 patients who underwent coronary artery bypass grafting (CABG) (25 673 [71.7%]) and heart valve (10 144 [28.3%]) procedures. All patients were opioid-naive within 180 days before the index procedure and filled an opioid prescription within 14 days after surgery. Opioid medications after cardiac surgery. The proportion of opioid-naive patients who developed new persistent opioid use within 90 to 180 days after surgery was determined. Oral morphine equivalents (OMEs) were calculated for the first opioid prescription filled after discharge. A multivariable logistic regression with cubic splines was used to analyze the association among the OMEs at discharge and likelihood of developing persistent opioid use. Of the 25 673 patients who underwent CABG, the mean (SD) age for those without (n = 23 064) vs with (n = 2609) persistent opioid use was 62.9 (9.8) years vs 61.6 (9.7) years, respectively, and the number who were men were 18 758 (81.3%) vs 1998 (76.6%). Of the 10 144 patients who underwent heart valve surgery, the mean (SD) age for those without (n = 9343) vs with (n = 821) persistent opioid use was 63.2 (12.4) years vs 61.2 (12.5) years, respectively, and the number who were men were 6378 (68.3%) vs 511 (62.2%). Persistent opioid use is a substantial concern after cardiac surgery and occurred in 2609 patients undergoing CABG (10.2%) and 821 valve surgery patients (8.1%; P = .001). The likelihood for developing persistent opioid use was decreased among heart valve surgery recipients (odds ratio [OR], 0.78; P < .001) and increased for patients who were women; younger; with preoperative congestive heart failure, chronic lung disease, diabetes, kidney failure, chronic pain, and alcoholism; and those taking preoperative benzodiazepines and muscle relaxants (women: OR, 1.15 [95% CI, 1.03-1.26]; younger age: OR, 1.02 [95% CI, 1.01-1.02]; congestive heart failure: OR, 1.17 [95% CI, 1.06-1.30]; chronic lung disease: OR, 1.32 [95% CI, 1.19-1.45]; diabetes: OR, 1.27 [95% CI, 1.15-1.40]; kidney failure: OR, 1.17 [95% CI, 1.00-1.37]; chronic pain: OR, 2.71 [95% CI, 2.10-3.56]; alcoholism: OR, 1.56 [95% CI, 1.23-2.00]; benzodiazepines: OR, 1.71 [95% CI, 1.52-1.91]; muscle relaxants: OR, 1.74 [95% CI, 1.51-2.02]; all P < .001). Furthermore, we found that when patients were prescribed more than approximately 300 mg of OMEs at discharge, they had a significantly increased risk of new persistent opioid use than with lower opioid prescriptions. Opioids are used extensively after cardiothoracic surgery and nearly 1 of 10 patients will continue to use opioids over 90 days after surgery. Furthermore, higher OMEs prescribed at discharge were significantly associated with developing persistent use. Centers must adopt protocols to increase patient education and limit opioid prescriptions after discharge.


Hepatitis B virus, hepatitis C virus and other blood-borne infections in healthcare workers: guidelines for prevention and management in industrialised countries.
The Viral Hepatitis Prevention Board (VHPB) convened a meeting of international experts from the public and private sectors in order to review and evaluate the epidemiology of blood-borne infections in healthcare workers, to evaluate the transmission of hepatitis B and C viruses as an occupational risk, to discuss primary and secondary prevention measures and to review recommendations for infected healthcare workers and (para)medical students. This VHPB meeting outlined a number of recommendations for the prevention and control of viral hepatitis in the following domains: application of standard precautions, panels for counselling infected healthcare workers and patients, hepatitis B vaccination, restrictions on the practice of exposure-prone procedures by infected healthcare workers, ethical and legal issues, assessment of risk and costs, priority setting by individual countries and the role of the VHPB. Participants also identified a number of terms that need harmonization or standardisation in order to facilitate communication between experts.


Growth and Maturation in Development: A Fly's Perspective.
In mammals like humans, adult fitness is improved due to resource allocation, investing energy in the developmental growth process during the juvenile period, and in reproduction at the adult stage. Therefore, the attainment of their target body height/size co-occurs with the acquisition of maturation, implying a need for coordination between mechanisms that regulate organismal growth and maturation timing. Insects like Drosophila melanogaster also define their adult body size by the end of the juvenile larval period. Recent studies in the fly have shown evolutionary conservation of the regulatory pathways controlling growth and maturation, suggesting the existence of common coordinator mechanisms between them. In this review, we will present an overview of the significant advancements in the coordination mechanisms ensuring developmental robustness in Drosophila. We will include (i) the characterization of feedback mechanisms between maturation and growth hormones, (ii) the recognition of a relaxin-like peptide Dilp8 as a central processor coordinating juvenile regeneration and time of maturation, and (iii) the identification of a novel coordinator mechanism involving the AstA/KISS system.


Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells.
Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation. We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis. We studied changes in mitochondrial morphology and in expression of markers for mitochondrial capacity, damage/biogenesis and fission/fusion in the human bronchial epithelial cell line BEAS-2B upon 6-months from ex-smoking COPD GOLD stage IV patients to age-matched smoking and never-smoking controls. We observed that long-term CSE exposure induces robust changes in mitochondrial structure, including fragmentation, branching and quantity of cristae. The majority of these changes were persistent upon CSE depletion. Furthermore, long-term CSE exposure significantly increased the expression of specific fission/fusion markers (Fis1, Mfn1, Mfn2, Drp1 and Opa1), oxidative phosphorylation (OXPHOS) proteins (Complex II, III and V), and oxidative stress (Mn-SOD) markers. These changes were accompanied by increased levels of the pro-inflammatory mediators IL-6, IL-8, and IL-1β. Importantly, COPD primary bronchial epithelial cells (PBECs) displayed similar changes in mitochondrial morphology as observed in long-term CSE-exposure BEAS-2B cells. Moreover, expression of specific OXPHOS proteins was higher in PBECs from COPD patients than control smokers, as was the expression of mitochondrial stress marker PINK1. The observed mitochondrial changes in COPD epithelium are potentially the consequence of long-term exposure to cigarette smoke, leading to impaired mitochondrial function and may play a role in the pathogenesis of COPD.


Cognitive behavioural therapy for post-stroke fatigue and sleep disturbance: a pilot randomised controlled trial with blind assessment.
The objective of this study was to evaluate the effectiveness of individual cognitive behavioural therapy (CBT) for post-stroke fatigue and sleep disturbance compared to treatment as usual (TAU). In a parallel two-group pilot randomised controlled trial of 15 participants, nine were allocated to eight weekly sessions of adapted CBT and six continued usual care rehabilitation. The primary outcome was the Fatigue Severity Scale (FSS-7) at two and four months from baseline. Secondary outcomes included measures of sleep, mood and quality of life. Outcomes were assessed by a rater who was blind to group membership. At the four-month endpoint, the CBT group demonstrated significantly reduced fatigue relative to TAU (FSS-7 mean difference: 1.92, 95% CI: 0.24 to 3.60). Significant group differences also emerged for sleep quality and depression, favouring the CBT group. Insomnia and physical quality of life improved immediately post-therapy but were no longer superior to TAU at follow-up. Overall, CBT is a promising treatment for improving post-stroke fatigue, sleep quality and depression. Gains were maintained for two months after therapy cessation and represented large treatment effects. These findings highlight the feasibility of the intervention and warrant extension to a phase III clinical trial.


Synthesis and characterization of amphiphilic reduced graphene oxide with epoxidized methyl oleate.
Amphiphilic reduced graphene oxide is obtained by oleo-functionalization with epoxidized methyl oleate (renewable feedstock) using a green process. The excellent diverse solvent-dispersivity of the oleo-reduced amphiphilic graphene and its reduction chemistry are confirmed in this study. Oleo-reduction of amphiphilic graphene is amenable to industrially viable processes to produce future graphene-based polymer composites and systems.