Quantitative MRI Helps to Detect Hip Ischemia: Preclinical Model of Legg-Calvé-Perthes Disease.
Purpose To determine whether quantitative MRI relaxation time mapping techniques can help to detect ischemic injury to the developing femoral head. Materials and Methods For this prospective animal study conducted from November 2015 to February 2018, 10 male 6-week-old piglets underwent an operation to induce complete right femoral head ischemia. Animals were humanely killed at 48 hours (n = 2) or 4 weeks (n = 8) after the operation, and the operated and contralateral-control femoral heads were harvested and frozen. Thawed specimens were imaged at 9.4-T MRI by using T1, T2, T1 in the rotating frame (T1ρ), adiabatic T1ρ, relaxation along a fictitious field (RAFF), and T2* mapping and evaluated with histologic analysis. Paired relaxation time differences between the operated and control femoral heads were measured in the secondary ossification center (SOC), epiphyseal cartilage, articular cartilage, and metaphysis and were analyzed by using a paired t test. Results In the SOC, T1ρ and RAFF had the greatest percent increases in the operated versus control femoral heads at both 48 hours (112% and 72%, respectively) and 4 weeks (74% and 70%, respectively). In the epiphyseal and articular cartilage, T2, T1ρ, and RAFF were similarly increased at both points (range, 24%-49%). At 4 weeks, T2, T1ρ, adiabatic T1ρ, and RAFF were increased in the SOC (P = .004, .018, < .001, and .001, respectively), epiphyseal cartilage (P = .009, .008, .011, and .007, respectively), and articular cartilage (P = .005, .016, .033, and .018, respectively). Histologic assessment identified necrosis in SOC and deep layer of the epiphyseal cartilage at both points. Conclusion T2, T1 in the rotating frame, adiabatic T1 in the rotating frame, and relaxation along a fictitious field maps are sensitive in helping to detect ischemic injury to the developing femoral head. © RSNA, 2018 Online supplemental material is available for this article.


Thoracic aortic atheroma severity predicts high-risk coronary anatomy in patients undergoing transesophageal echocardiography.
We hypothesized a relationship between severity of thoracic aortic atheroma (AA) and prevalence of high-risk coronary anatomy (HRCA). We investigated AA diagnosed by transesophageal echocardiography and HRCA diagnosed by coronary angiography in 187 patients. HRCA was defined as ≥ 50% stenosis of the left main coronary artery or significant 3-vessel coronary artery disease (≥ 70% narrowing). HRCA was present in 45 of 187 patients (24%). AA severity was grade I in 55 patients (29%), grade II in 71 patients (38%), grade III in 52 patients (28%), grade IV in 5 patients (3%), and grade V in 4 patients (2%). The area under receiver operating characteristic curve for AA grade predicting HRCA was 0.83 (p = 0.0001). The cut-off points of AA to predict HRCA was > II grade. The sensitivity and specificity of AA > grade II to predict HRCA were 76% and 81%, respectively. After adjustment for 10 variables with significant differences by univariate regression, AA > grade II was related to HRCA by multivariate regression (odds ratio = 7.5, p< 0.0001). During 41-month follow-up, 15 of 61 patients (25%) with AA >grade II and 10 of 126 patients (8%) with AA grade ≤ 2 died (p= 0.004). Survival by Kaplan-Meier plot in patients with AA > grade II was significantly decreased compared to patients with AA ≤ grade II (p= 0.002). AA > grade II is associated with a 7.5 times increase in HRCA and with a significant reduction in all-cause mortality.


Revisiting the Prevalence of Autism Spectrum Disorder among Omani Children: A multicentre study.
This study aimed to provide an updated estimate of the prevalence of autism spectrum disorder (ASD) among Omani children. This retrospective descriptive study was conducted from December 2011 to December 2018. Data were retrieved from the three main autism diagnostic centres in Oman: Sultan Qaboos University Hospital, Royal Hospital and Al-Massarah Hospital. The ASD diagnosis was made by experienced clinicians based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The overall population prevalence estimates per 10,000 children aged 0-14 years old in Oman were calculated using the denominator of the mid-period population data. A total of 1,705 ASD cases were identified with the majority of cases being male (78.1%). The overall prevalence rate of ASD was estimated at 20.35 per 10,000 children (95% confidence interval: 19.39-21.32) between 2012-2018. Boys were found to have a 3.4-fold higher prevalence of ASD than girls (31.23/10,000 versus 9.07/10,000). Regionally, the majority of cases were found in the capital, Muscat, where the highest prevalence was 36.51 cases per 10,000 children. The prevalence of ASD among Omani children is 15-fold higher than estimates from 2011. This increase can be attributed to improvements in diagnostic services, increased awareness of ASD, better screening programmes and changes in diagnostic criteria. In addition, this increase in prevalence suggests a need for a registry of developmental disabilities and more extensive diagnostic and rehabilitation services in Oman.


Altered Brain Criticality in Schizophrenia: New Insights From Magnetoencephalography.
Schizophrenia has a complex etiology and symptomatology that is difficult to untangle. After decades of research, important advancements toward a central biomarker are still lacking. One of the missing pieces is a better understanding of how non-linear neural dynamics are altered in this patient population. In this study, the resting-state neuromagnetic signals of schizophrenia patients and healthy controls were analyzed in the framework of criticality. When biological systems like the brain are in a state of criticality, they are thought to be functioning at maximum efficiency (e.g., optimal communication and storage of information) and with maximum adaptability to incoming information. Here, we assessed the self-similarity and multifractality of resting-state brain signals recorded with magnetoencephalography in patients with schizophrenia patients and in matched controls. Schizophrenia patients had similar, although attenuated, patterns of self-similarity and multifractality values. Statistical tests showed that patients had higher values of self-similarity than controls in fronto-temporal regions, indicative of more regularity and memory in the signal. In contrast, patients had less multifractality than controls in the parietal and occipital regions, indicative of less diverse singularities and reduced variability in the signal. In addition, supervised machine-learning, based on logistic regression, successfully discriminated the two groups using measures of self-similarity and multifractality as features. Our results provide new insights into the baseline cognitive functioning of schizophrenia patients by identifying key alterations of criticality properties in their resting-state brain data.


Measurement of the electrically evoked compound action potential via a neural response telemetry system.
The main aim of this study was to validate a new technique, neural response telemetry (NRT), for measuring the electrically evoked compound action potential in adult cochlear implant users via their Nucleus C124M implant. Thirty-eight adults were evaluated with a variety of measurement procedures with the NRT software. Electrically evoked compound action potentials were obtained in 31 of the 38 adults (81.6%) and in 132 of the 160 electrodes (82.5%) tested. In addition to validating this technique, we also established a set of default clinical test parameters.


Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice.
An accumulating body of evidence suggests that the endocannabinoid system plays a significant role in pathophysiological processes and impacts disease severity. Here we investigate the possible role of a cannabinoid receptor type 2 (CB2) functional variant in determining disease severity and the potential pharmacological therapeutic effects of CB2 activation in viral respiratory infection. The common missense variant (CAA/CGG; Q63R) of the gene-encoding CB2 receptor (CNR2) was evaluated in 90 inpatient and 90 outpatient children with acute respiratory tract infection (ARTI). The frequency distribution of respiratory syncytial virus (RSV)-the main cause of severe cases of bronchiolitis and pneumonia in children-was studied in all collected samples. The mechanism through which CB2 affects clinical outcomes in case of RSV infection was studied in Balb/c mice model using AM630 as a CB2 antagonist. The potential therapeutic effect of CB2 activation during RSV infection was studied using a selective agonist, JWH133. The CB2 Q63R variation was associated with increased risk of hospitalization in children with ARTI. Children carrying the QQ genotype were more prone to developing severe ARTI (OR = 3.275, 95% CI: 1.221-8.705; p = 0.019). Of all the children enrolled in the study, 83 patients (46.1%) were found positive for RSV infection. The associated risk of developing severe ARTI following RSV infection increased more than two-fold in children carrying the Q allele (OR = 2.148, 95% CI: 1.092-4.224; p = 0.026). In mice, the blockade of CB2 by AM630 during RSV infection enhanced the influx of BAL cells and production of cytokines/chemokines while exaggerating lung pathology. CB2 activation by JWH133 reduces the influx of BAL cells and production of cytokines/chemokines while alleviating lung pathology. Collectively, CB2 is associated with RSV severity during infancy and may serve as a therapeutic target in RSV infection through the alleviation of virus-associated immunopathology.


The frustrating effects of just missing the jackpot: slot machine near-misses trigger large skin conductance responses, but no post-reinforcement pauses.
Near-misses in slot machines resemble jackpot wins but fall just short. Previous research has demonstrated that near-misses are behaviorally reinforcing despite the absence of monetary reward. We assessed the hedonic properties of near-misses by measuring the time between outcome delivery and the initiation of the next spin-the post-reinforcement pause (PRP) and skin conductance responses (SCRs) for losses, near-misses, and a range of wins (5, 15, 25, 50 or 250 credits) while participants (N = 122) played a slot machine simulator. PRPs and SCRs were compared for 40 low frequency and 22 high frequency slots players who were non-problem gamblers, 37 at risk players, and 23 problem gamblers. For winning outcomes, PRPs and SCRs tracked monotonically with win size such that progressively larger wins were associated with progressively larger PRPs and SCRs. Near-misses with jackpot symbols landing on the first two reels had significantly larger SCRs than regular losses, and other types of near misses. Crucially, PRPs for this kind of near-miss were significantly smaller than all wins, and when non-parametric statistics were used, significantly smaller than regular losses. This pattern of large SCRs and small PRPs suggest that these are highly frustrating outcomes that stimulate appetitive components of the reward system to promote continued gambling.


Generation and functional in vivo characterization of a lipid kinase defective phosphatidylinositol 3-kinase Vps34p of Candida albicans.
The phosphatidylinositol (PI) 3-kinase Vps34p of Candida albicans has lipid kinase and autophosphorylation activity and is involved in virulence and vesicular protein transport. In order to characterize the roles of lipid kinase activity, a chimeric Vps34 protein was created which lacks lipid kinase but retains autophosphorylation activity. To this end, six amino acids within the putative lipid-binding site of Vps34p were replaced by the homologous region of the PI 3-kinase-like C. albicans Tor protein. The resulting chimeric Vps34T protein was recombinantly expressed in Escherichia coli and shown to lack lipid kinase activity. The corresponding chimeric VPS34TOR gene was inserted into the genome of C. albicans, and this lipid-kinase-defective strain had a distinctive phenotype compared to those of the wild-type strain SC5314 and the vps34 null mutant. The lipid-kinase-defective strain was non-virulent, and showed altered hyphal growth, reduced adherence, as well as defective vacuole morphology and endosomal vesicle transport. These results demonstrate an important role for the lipid kinase activity of Vps34p in virulence and vesicular protein transport. On the other hand, the lipid-kinase-defective strain and the vps34 null mutant differ in their temperature- and osmotic-stress response. This indicates a possible role for activities different from the lipid kinase function of Vps34p.


An analysis of mutative sigma-self-adaptation on linear fitness functions.
This paper investigates sigma-self-adaptation for real valued evolutionary algorithms on linear fitness functions. We identify the step-size logarithm log sigma as a key quantity to understand strategy behavior. Knowing the bias of mutation, recombination, and selection on log sigma is sufficient to explain sigma-dynamics and strategy behavior in many cases, even from previously reported results on non-linear and/or noisy fitness functions. On a linear fitness function, if intermediate multi-recombination is applied on the object parameters, the i-th best and the i-th worst individual have the same sigma-distribution. Consequently, the correlation between fitness and step-size sigma is zero. Assuming additionally that sigma-changes due to mutation and recombination are unbiased, then sigma-self-adaptation enlarges sigma if and only if mu < lambda/2, given (mu, lambda)-truncation selection. Experiments show the relevance of the given assumptions.


Insights into the molecular interaction between sucrose and α-chymotrypsin.
One of the most important purposes of enzyme engineering is to increase the thermal and kinetic stability of enzymes, which is an important factor for using enzymes in industry. The purpose of the present study is to achieve a higher thermal stability of α-chymotrypsin (α-Chy) by modification of the solvent environment. The influence of sucrose was investigated using thermal denaturation analysis, fluorescence spectroscopy, circular dichroism, molecular docking and molecular dynamics (MD) simulations. The results point to the effect of sucrose in enhancing the α-Chy stability. Fluorescence spectroscopy revealed one binding site that is dominated by static quenching. Molecular docking and MD simulation results indicate that hydrogen bonding and van der Waals forces play a major role in stabilizing the complex. Tm of this complex was enhanced due to the higher H-bond formation and the lower surface hydrophobicity after sucrose modification. The results show the ability of sucrose in protecting the native structural conformation of α-Chy. Sucrose was preferentially excluded from the surface of α-Chy which is explained by the higher tendency of water toward favorable interactions with the functional groups of α-Chy than with sucrose.


Perception of pointing from biological motion point-light displays in typically developing children and children with autism spectrum disorder.
We examined whether the movement involved in a pointing gesture, depicted using point-light displays, is sufficient to cue attention in typically developing children (TD) and children with autism spectrum disorder (ASD) (aged 8-11 years). Using a Posner-type paradigm, a centrally located display indicated the location of a forthcoming target on 80% of trials and the opposite location on 20% of trials. TD children, but not children with ASD, were faster to identify a validly cued target than an invalidly cued target. A scrambled version of the point-light pointing gesture, retaining individual dot speed and direction of movement but not the configuration, produced no validity effect in either group. A video of a pointing gesture produced validity effects in both groups.


Understanding chromate reaction kinetics with corroding iron media using Tafel analysis and electrochemical impedance spectroscopy.
The kinetics of chromate removal from contaminated water by zerovalent iron media are not well understood. This study investigated the reactions occurring on iron surfaces in chromate solutions in order to understand the removal kinetics and to assess the long-term ability of zerovalent iron for removing Cr(VI) from contaminated water. Tafel polarization analysis and electrochemical impedance spectroscopy were used to determine the corrosion rates and charge-transfer resistances associated with Cr(VI) removal by iron wires suspended in electrolyte solutions with initial Cr(VI) concentrations of 10,000 microg/L. The condition of the iron surfaces at the time of their exposure to chromate determined the effectiveness of the iron for chromate removal. Both iron coated with a water-formed oxide and initially oxide-free iron were effective for chromate removal. However, iron coated with an air-formed oxide was an order of magnitude less effective for removing soluble chromium. Although iron with the air-formed oxide was largely passivated with respect to chromate removal, its overall rate of corrosion was similar to that for iron with the other initial surface conditions. This indicates that water, but not chromate, was able to penetrate the air-formed oxide coating and access cathodic sites. For all initial surface conditions, addition of chromate decreased the corrosion rate by increasing the corrosion potential and the anodic charge transfer resistance. Although Cr(VI) is a strong oxidant rates of iron corrosion were not proportional to the aqueous Cr(VI) concentrations due to anodic control of iron corrosion. Under anodically controlled conditions, the rate of corrosion was limited by the rate at which Fe2+ could be released at anodic sites and not by the rate at which oxidants were able to accept electrons. This study shows that the zero order removal kinetics of Cr(VI) by iron media can be explained by anodic control of iron corrosion and the concomitant anodic control of Cr(VI) reduction.


Adenosine, lidocaine, and Mg2+ (ALM™) increases survival and corrects coagulopathy after eight-minute asphyxial cardiac arrest in the rat.
No drug therapy has demonstrated improved survival following cardiac arrest (CA) of cardiac or noncardiac origin. In an effort to translate the cardiorescue properties of Adenocaine (adenosine and lidocaine) and magnesium sulfate (ALM) from cardiac surgery and hemorrhagic shock to resuscitation, we examined the effect of ALM on hemodynamic rescue and coagulopathy following asphyxial-induced CA in the rat. Nonheparinized animals (400-500 g, n = 39) were randomly assigned to 0.9% saline (n = 12) and 0.9% saline ALM (n = 10) groups. After baseline data were acquired, the animal was surface cooled (33°C-34°C) and the ventilator line clamped for 8 min inducing CA; 0.5 mL of solution was injected intravenously followed by 60-s chest compressions (300/min), and rats were rewarmed. Return of spontaneous circulation (ROSC), mean arterial pressure, heart rate, and rectal temperature were recorded for 2 h. Additional rats were randomized for rotation thromboelastometry measurements (n = 17). Rats treated with ALM had a significant survival benefit (100% ALM vs. 67% controls achieved ROSC) and generated a higher mean arterial pressure than did controls after 75 min (81 vs. 72 mmHg at 120 min, P < 0.05). In all rats, rotation thromboelastometry lysis index decreased during CA, implying hyperfibrinolysis. Control ROSC survivors displayed hypocoagulopathy (prolonged EXTEM/INTEM clotting time, clot formation time, prothrombin time, activated partial thromboplastin time), decreased maximal clot firmness, lowered elasticity, and lowered clot amplitudes but no change in lysis index. These coagulation abnormalities were corrected by ALM at 120 min after ROSC. Small bolus of 0.9% NaCl ALM improved survival and hemodynamics following nonhemorrhagic, asphyxial CA and corrected prolonged clot times and clot retraction compared with controls.


Postural changes in blood pressure and incidence of ischemic stroke subtypes: the ARIC study.
The relation of orthostatic blood pressure decrease, or increase, with occurrence of ischemic stroke subtypes has not been examined. We investigated the association of orthostatic blood pressure change (within 2 minutes after supine to standing) obtained at baseline (1987 to 1989) in the Atherosclerosis Risk in Communities Study with incidence of ischemic stroke subtypes through 2007. Among 12 817 black and white individuals without a history of stroke at baseline, 680 ischemic strokes (153 lacunar, 383 nonlacunar thrombotic, and 144 cardioembolic strokes) occurred during a median follow-up of 18.7 years. There was a U-shaped association between orthostatic systolic blood pressure change and lacunar stroke incidence (quadratic P=0.004). In contrast, orthostatic systolic blood pressure decrease of 20 mm Hg or more was associated with increased occurrence of nonlacunar thrombotic and cardioembolic strokes independent of sitting systolic blood pressure, antihypertensive medication use, diabetes, and other lifestyle, physiological, biochemical, and medical conditions at baseline (for nonlacunar thrombotic: hazard ratio, 2.02; 95% CI, 1.43 to 2.84; for cardioembolic: hazard ratio, 1.85, 95% CI, 1.01 to 3.39). Orthostatic diastolic blood pressure decrease was associated with increased risk of nonlacunar thrombotic and cardioembolic strokes; the hazard ratios (95% CI) associated with 10 mm Hg lower orthostatic diastolic blood pressure (continuous) were 1.26 (1.06 to 1.50) and 1.41 (1.06 to 1.88), respectively, in fully adjusted models. In conclusion, the present study found that nonlacunar ischemic stroke incidence was positively associated with an orthostatic decrease of systolic and diastolic blood pressure, whereas greater lacunar stroke incidence was associated with both orthostatic increases and decreases in systolic blood pressure.


A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): part 5 - surgical and injection-based interventions for chronic WAD.
Whiplash-associated disorder (WAD) represents a significant public health problem, resulting in substantial social and economic costs throughout the industrialized world. While many treatments have been advocated for patients with WAD, scientific support regarding their effectiveness is often lacking. A systematic review was conducted to evaluate the strength of evidence associated with various WAD therapies. Multiple databases (including Web of Science, EMBASE and PubMed) were searched to identify all studies published from January 1980 through March 2009 that evaluated the effectiveness of any well-defined treatment for acute (less than two weeks), subacute (two to 12 weeks) or chronic (more than 12 weeks) WAD. The present article, the fifth in a five-part series, evaluates the evidence for surgical and injection-based interventions initiated during the chronic phase of WAD. Twenty-five studies were identified that met the inclusion criteria, six of which were randomized controlled trials with 'good' overall methodological quality (median Physiotherapy Evidence Database score of 7.5). For the treatment of chronic WAD, there was moderate evidence supporting radiofrequency neurotomy as an effective treatment for whiplash-related pain, although relief is not permanent. Sterile water injections have been demonstrated to be superior to saline injections; however, it is not clear whether this treatment is actually beneficial. There was evidence supporting a wide range of other interventions (eg, carpal tunnel decompression) with each of these evaluated by a single nonrandomized controlled trial. There is contradictory evidence regarding the effectiveness of botulinum toxin injections, and cervical discectomy and fusion. The evidence is not yet strong enough to establish the effectiveness of any of these treatments; of all the invasive interventions for chronic WAD, radiofrequency neurotomy appears to be supported by the strongest evidence. Further research is required to determine the efficacy and the role of invasive interventions in the treatment of chronic WAD.


Meningococcal antigen in diagnosis and treatment of group A meningococcal infections.
Meningococcal antigen was measured by countercurrent immunoelectrophoresis in the blood and cerebrospinal fluid of 200 patients with group A meningococcal meningitis. Antigen was detected in the blood of 27 (13.5 per cent) patients. These patients had a worse prognosis and a higher incidence of allergic complications, such as arthritis and vasculitis, about 5 days after the start of antibiotic treatment. Antigen was found in the CSF of 129 (67.5 per cent) patients); antigen often persisted in the cerebrospinal fluid despite antibiotic treatment before admission. A combination of immunoelectrophoresis and routine bacteriologic study was used in the diagnosis of 162 (84.8 per cent) patients with meningococcal meningitis. High levels of antigen and a slow antigen disappearance were associated with neurologic damage. The antigen is stable and may be detected from specimens of cerebrospinal fluid dried on filter paper.


Psoriatic arthritis. Follow-up study.
227 patients with psoriasis and various forms of arthritis have been kept under review. Psoriasis and inflammatory arthropathy was present in 168 patients, of whom 94 have been followed up for more than 10 years. An arthritis indistinguishable from rheumatoid disease was present in 78%, distal joint arthritis in 16-6%, and deforming arthritis in 4-8%. There was a female predominance in the sex ratio of patients, although males predominated in the distal joint group (male:female 1-5:1). The peak age of onset was between 36 and 45 years, although in the deforming group the arthritis began before the age of 20 three times as commonly as it did in the indistinguishable group. Onset was acute in nearly half of the patients. At onset the distal joints were affected in one-third of the distal joint group. A synchronous onset of skin and joint changes was uncommon. Skin lesions usually preceded the arthritis but occurred after onset in 16%. Apart from in the deforming group, the arthritis was mild, judged by the number of admissions to hospital for treatment of the joint disease, and the time off work. Deterioration clinically and radiographically occurred in only a small portion of the distal joint and indistinguishable groups. Antimalarial drugs have been used in 7 patients, with deterioration of the skin condition in 4. Uveitis occurred particularly in the men of all three groups, but was most frequent in those with deforming arthritis. A family history of psoriasis was obtained in 26% of first-degree relatives and 13% of second-degree relatives. A history of polyarthritis was most common in patients in the deforming group. The sheep cell agglutination test was negative in the majority, but was positive in 16% of the indistinguishable group, fluctuating in a further 10%. A small number of joints only deteriorated radiographically (10% of the distal and indistinguishable groups). The men in the distal group showed greater radiographic changes and more deterioration in the terminal interphalangeal joints of the fingers than the women. Similarly they showed more deterioration of the metatarsophalangeal joints than the women. 18 patients died, one with gastric haemorrhage resulting from treatment of exfoliative psoriasis with immunosuppressive therapy, and 2 from bronchopneumonia thought to be related to immobility caused by the arthritis.


Post placement positional atrial fibrillation and peripherally inserted central catheters.
Arrhythmias are common in hospitalized patients and during surgery. We present a case of positional atrial arrhythmia related to a peripherally inserted central catheter (PICC). There are other documented case reports of ventricular tachycardia precipitated by body position changes with a PICC. The immediate correction of the arrhythmia with repositioning of the PICC strongly points to the PICC as the cause. This highlights the potential seriousness of cardiac arrhythmias precipitated by PICCs as well as the need for careful catheter placement and perioperative maintenance. Practitioners should consider PICC line tip position as a rare cause of positional atrial arrhythmias.


Nutritional support for children during critical illness: European Society of Pediatric and Neonatal Intensive Care (ESPNIC) metabolism, endocrine and nutrition section position statement and clinical recommendations.
Nutritional support is considered essential for the outcome of paediatric critical illness. There is a lack of methodologically sound trials to provide evidence-based guidelines leading to diverse practices in PICUs worldwide. Acknowledging these limitations, we aimed to summarize the available literature and provide practical guidance for the paediatric critical care clinicians around important clinical questions many of which are not covered by previous guidelines. To provide an ESPNIC position statement and make clinical recommendations for the assessment and nutritional support in critically ill infants and children. The metabolism, endocrine and nutrition (MEN) section of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) generated 15 clinical questions regarding different aspects of nutrition in critically ill children. After a systematic literature search, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was applied to assess the quality of the evidence, conducting meta-analyses where possible, to generate statements and clinical recommendations, which were then voted on electronically. Strong consensus (> 95% agreement) and consensus (> 75% agreement) on these statements and recommendations was measured through modified Delphi voting rounds. The final 15 clinical questions generated a total of 7261 abstracts, of which 142 publications were identified relevant to develop 32 recommendations. A strong consensus was reached in 21 (66%) and consensus was reached in 11 (34%) of the recommendations. Only 11 meta-analyses could be performed on 5 questions. We present a position statement and clinical practice recommendations. The general level of evidence of the available literature was low. We have summarised this and provided a practical guidance for the paediatric critical care clinicians around important clinical questions.


Antiamnesic Effect of Broccoli (Brassica oleracea var. italica) Leaves on Amyloid Beta (Aβ)1-42-Induced Learning and Memory Impairment.
To examine the antiamnesic effects of broccoli (Brassica oleracea var. italica) leaves, we performed in vitro and in vivo tests on amyloid beta (Aβ)-induced neurotoxicity. The chloroform fraction from broccoli leaves (CBL) showed a remarkable neuronal cell-protective effect and an inhibition against acetylcholinesterase (AChE). The ameliorating effect of CBL on Aβ1-42-induced learning and memory impairment was evaluated by Y-maze, passive avoidance, and Morris water maze tests. The results indicated improving cognitive function in the CBL group. After the behavioral tests, antioxidant effects were detected by superoxide dismutase (SOD), oxidized glutathione (GSH)/total GSH, and malondialdehyde (MDA) assays, and inhibition against AChE was also presented in the brain. Finally, oxo-dihydroxy-octadecenoic acid (oxo-DHODE) and trihydroxy-octadecenoic acid (THODE) as main compounds were identified by quadrupole time-of-flight ultraperformance liquid chromatography (Q-TOF UPLC-MS) analysis. Therefore, our studies suggest that CBL could be used as a natural resource for ameliorating Aβ1-42-induced learning and memory impairment.


Instability, dynamics, and morphology of thin slipping films.
Based on the linear stability and nonlinear simulations, we show that the surface instability, dynamics, and morphology of supported thin liquid films are profoundly altered by the presence of slippage on the substrate. A general dispersion equation for flow in slipping thin films is derived and simplified to identify three different regimes of slippage (weak, moderate, and strong) and obtain the length and time scales of instability in them. For illustration, the ubiquitous van der Waals interactions have been employed. Different regimes of slip-flow can be predicted based on a nondimensional parameter, xi, which is a function of slip length, film thickness, intermolecular potential, and interfacial tension. Two distinct transitions from weak to moderate slip and from moderate to strong slip occur at xiT1 approximately 0.01 and xiT2 approximately 500, respectively. More specifically, a decrease in film thickness causes transitions from weak to moderate to strong slip regime. Even a weak slippage causes faster breakup of a thin film, whereas slippage beyond a transition value (slip length, bT1) increases the length scale of instability and reduces the number density of holes compared to the nonslipping case. Strong slippage produces holes faster, and the holes are fewer in number and have less developed rims. The exponents for the length scale (lambdam infinity h0n; h0 is film thickness) and time scale of instability (tr infinity h0m) change nonmonotonically with slippage (for nonretarded van der Waals instability, n E (1.25, 2), m E (3, 6)). Retardation in van der Waals potential increases the exponents (n E (1.5, 2.5), m E (5, 8)). The initial stage of evolution of a slipping film, simulated based on nonlinear equations, follows the length scale and time scale of instability, close to the prediction of linear analysis. It is hoped that the present analysis will help in better interpretation of thin film experiments, in estimation of slippage, and in the determination of intermolecular forces from the length and time scales of the instability.


Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma.
Glioblastoma is one of the most malignant types of human cancer, and the prognosis is poor. The development and validation of novel molecular imaging biomarkers has the potential to improve tumor detection, grading, risk stratification, and treatment monitoring of gliomas. The aim of this study was to explore the potential of PET imaging of the urokinase-type plasminogen activator receptor (uPAR) in glioblastoma. The uPAR messenger RNA expression of tumors from 19 glioblastoma patients was analyzed, and a cell culture derived from one of these patients was used to establish an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and, for comparison, O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of (64)Cu-NOTA-AE105 was confirmed by alignment of hematoxylin- and eosin-stained and uPAR immunohistochemistry-stained slides of the brain with the activity distribution as determined using autoradiography. uPAR expression was found in all 19 glioblastoma patient tumors, and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with (64)Cu and (68)Ga was straightforward, resulting in a specific activity of approximately 20 GBq/μmol and a radiochemical purity of more than 98% for (64)Cu-NOTA-AE105 and more than 97% for (68)Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both (68)Ga-NOTA-AE105 and (64)Cu-NOTA-AE105. Absolute uptake in tumor was higher for (18)F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for (64)Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or (68)Ga-NOTA-AE105 (0.4 ± 0.1 %ID/g). A similar pattern was observed in background brain tissue, where uptake was 1.9 ± 0.1 %ID/g for (18)F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for (68)Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for (64)Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both (68)Ga-NOTA-AE105 (7.6 ± 2.1, P < 0.05) and (64)Cu-NOTA-AE105 (10.6 ± 2.3, P < 0.01) than for (18)F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of (64)Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. On the basis of our translational study, uPAR PET may be a highly promising imaging biomarker for glioblastoma. Further clinical exploration of uPAR PET in glioblastoma is therefore justified.


Influence of comorbidity and age on 1-, 2-, and 3-month postoperative mortality rates in gastrointestinal cancer patients.
Studies on the impact of comorbidity and age on postoperative outcome after gastrointestinal tumor resection are scarce. In this study we investigated the impact of comorbidity and age on 30-, 60-, and 90-day mortality after resection of esophageal, gastric, periampullary, colon, and rectal cancer. The study included 8,583 patients recorded in the population-based Netherlands Cancer Registry, regions Eindhoven (Eindhoven Cancer Registry) and Mid and South Limburg, who underwent resection for cancer stage I-III. Patients were diagnosed between 2005 and 2010. Age was categorized as <65, 65-74, and ≥75 years. Comorbidity was present in more than two-thirds (n = 5,910) of patients. The 30-day mortality rates ranged from 0.5 % for rectal cancer patients <65 years to 12.8 % for gastric cancer patients ≥75 years. Patients with comorbidity who underwent esophageal tumor resection had the highest mortality rates, ranging from 8.4 % for 30-day to 12.0 % for 90-day mortality, while rectal cancer patients had the lowest rates, that is, 4.3-6.4 %, respectively. In multivariable analyses, cardiac disease (odds ratio [OR] = 1.74, 95 % confidence interval [95 % CI] = 1.32-2.30), vascular disease (OR = 1.41, 95 % CI = 1.02-1.95) and previous malignancies (OR = 1.38, 95 % CI = 1.02-1.86) in colon cancer, and cardiac disease (OR = 1.81, 95 % CI = 1.10-2.98) and vascular disease (OR = 1.95, 95 % CI = 1.11-3.42) in rectal cancer were associated with the highest 30-day mortality. Postoperative mortality extends beyond 30 days. Comorbidity and older age are associated with early postoperative mortality after gastrointestinal cancer resection. Underlying comorbidity should be identified preoperatively with attention to patients' specific needs to optimally attenuate risk prior to surgery. A less aggressive treatment approach may well be considered in these groups.


Improved Survival beyond 28 Days up to 1 Year after CytoSorb Treatment for Refractory Septic Shock: A Propensity-Weighted Retrospective Survival Analysis.
It is currently unknown whether CytoSorb treatment for septic shock improves long-term survival beyond 28 days from intensive care unit (ICU) admission and which factors determine outcome. This was a long-term follow-up retrospective analysis of patients with septic shock who were treated with continuous renal replacement therapy (CRRT) + CytoSorb (n = 67) or CRRT alone (n = 49). These patients were previously analyzed for 28-day mortality. The primary outcome was the time to long-term all-cause mortality. Factors associated with time to event were analyzed both weighted by stabilized inverse probability of treatment weights (sIPTW) as well as unweighted stratified by therapy received. The median follow-up for the total cohort was 30 days (interquartile range [IQR]: 5-334, maximum 1,059 days) after ICU admission and 333 days (IQR: 170-583) for those who survived beyond 28 days (n = 59). Survival beyond 28 days was sustained up to 1 year after ICU admission for both treatment regimens: 80% (standard error [SE] 7%) vs. 87% (SE 7%), for CytoSorb vs. CRRT, respectively, p = 0.853. By sIPTW, CytoSorb was significantly associated with long-term outcome compared to CRRT (adjusted hazard ratio [aHR] 0.59, 95% confidence interval [CI] 0.37-0.93, p = 0.025). Independent factors associated with long-term outcome in CytoSorb-treated patients were baseline log10 lactate levels (aHR 5.1, p = 0.002), age in the presence of comorbidity (aHR 2.60, p = 0.013), and presence of abdominal sepsis (aHR 0.34, p = 0.004). A lactate level above 6.0 mmol/L at the start of CytoSorb therapy had a positive predictive value of 79% for mortality (p = 0.013). Survival is achieved with CytoSorb and CRRT for patients with septic shock beyond 28 days from ICU admission and may be improved for CytoSorb treatment. Lactate levels above 6.0 mmol/L at the start of CytoSorb therapy are predictive of worse outcome with high specificity and positive predictive value.


Contextualised strategies to increase childhood and adolescent vaccination coverage in South Africa: a mixed-methods study.
Despite the unparalleled success of immunisation in the control of vaccine preventable diseases, immunisation coverage in South Africa remains suboptimal. While many evidence-based interventions have successfully improved vaccination coverage in other countries, they are not necessarily appropriate to the immunisation needs, barriers and facilitators of South Africa. The aim of this research is to investigate barriers and facilitators to optimal vaccination uptake, and develop contextualised strategies and implementation plans to increase childhood and adolescent vaccination coverage in South Africa. The study will employ a mixed-methods research design. It will be conducted over three iterative phases and use the Adopt, Contextualise or Adapt (ACA) model as an overarching conceptual framework. Phase 1 will identify, and develop a sampling frame of, immunisation stakeholders involved in the design, planning and implementation of childhood and human papillomavirus immunisation programmes in South Africa. Phase 2 will identify the main barriers and facilitators to, and solutions for, increasing vaccination coverage. This phase will comprise exploratory qualitative research with stakeholders and a review of existing systematic reviews on interventions for improving vaccination coverage. Using the findings from Phase 2 and the ACA model, Phase 3 will develop a set of proposed interventions and implementation action plans for improving immunisation coverage in South Africa. These plans will be discussed, revised and finalised through a series of participatory stakeholder workshops and an online questionnaire, conducted as part of Phase 3. Ethical approval was obtained from the South African Medical Research Council (EC018-11/2018). No risks to participants are expected. Various steps will be taken to ensure the anonymity and confidentiality of participants. The study findings will be shared at stakeholder workshops, the website of Cochrane South Africa and academic publications and conferences.


Anti-IL-12 and anti-TNF antibodies synergistically suppress the progression of murine collagen-induced arthritis.
The co-ordinate role of the Th1 cytokine IL-12 and the proinflammatory cytokine TNF in arthritis was explored using the DBA/1 mouse model, collagen-induced arthritis (CIA). In this study, mice with established arthritis were treated with anti-IL-12 and/or anti-TNF antibodies for 10 days from the onset of disease. Clinical assessment showed that the combined antibody treatment ameliorated disease severity to a greater extent than anti-TNF alone. Supporting these observations, histological analysis revealed that there was a reduced joint damage in the mice that received combined anti-IL-12 and anti-TNF treatment, compared to the other treatment groups. Anti-IL-12 had no statistically significant effect on the clinical outcome of disease. The combination of anti-IL-12 and anti-TNF treatment was found to reduce collagen type II (CII)-specific lymph node cell IFN-gamma production and proliferation, as well as decrease the anti-CII IgG2a:IgG1 ratio more effectively than either treatment alone. When the antibodies were added to synovial cells from arthritic mice and bone marrow macrophages in vitro, anti-TNF diminished IL-12 production, but anti-IL-12 had no effect on TNF production. These data suggest that, through the partial regulation of IL-12, TNF modulates the immune response in arthritis, as well as the inflammatory response. The synergistic action of anti-TNF and anti-IL-12 on CIA may provide a new therapeutic approach for treating rheumatoid arthritis.


Brain ventricular enlargement in human and murine acute intermittent porphyria.
The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.


Making researchers responsible: attributions of responsibility and ambiguous notions of culture in research codes of conduct.
Research codes of conduct offer guidance to researchers with respect to which values should be realized in research practices, how these values are to be realized, and what the respective responsibilities of the individual and the institution are in this. However, the question of how the responsibilities are to be divided between the individual and the institution has hitherto received little attention. We therefore performed an analysis of research codes of conduct to investigate how responsibilities are positioned as individual or institutional, and how the boundary between the two is drawn. We selected 12 institutional, national and international codes of conduct that apply to medical research in the Netherlands and subjected them to a close-reading content analysis. We first identified the dominant themes and then investigated how responsibility is attributed to individuals and institutions. We observed that the attribution of responsibility to either the individual or the institution is often not entirely clear, and that the notion of culture emerges as a residual category for such attributions. We see this notion of responsible research cultures as important; it is something that mediates between the individual level and the institutional level. However, at the same time it largely lacks substantiation. While many attributions of individual and institutional responsibility are clear, the exact boundary between the two is often problematic. We suggest two possible avenues for improving codes of conduct: either to clearly attribute responsibilities to individuals or institutions and depend less on the notion of culture, or to make culture a more explicit concern and articulate what it is and how a good culture might be fostered.


Stereoselective palladium-catalyzed carbocyclization of allenic allylic carboxylates.
Palladium(0)-catalyzed reaction of allene-substituted allylic carboxylates 3-8 employing 2-5 mol % of Pd(dba)(2) in refluxing toluene leads to the carbocyclization and elimination of carboxylic acid to give bicyclo[4.3.0]nonadiene and bicyclo[5.3.0]decadiene derivatives (12-17). The carbon-carbon bond formation is stereospecific, occurring syn with respect to the leaving group. Addition of maleic anhydride as a ligand to the above-mentioned procedures changed the outcome of the reaction, and under these conditions 3-5 afforded cycloisomerized products 21-23. The experimental results are consistent with a mechanism involving oxidative addition of the allylic carboxylate to Pd(0) to give an electron-deficient (pi-allyl)palladium intermediate, followed by nucleophilic attack by the allene on the face of the pi-allyl opposite to that of the palladium atom. Furthermore, it was found that the Pd(dba)(2)-catalyzed cyclization of the trans-cycloheptene derivative (trans-8) can be directed to give either the trans-fused (trans-17) or the cis-fused (cis-17) ring system by altering the solvent. The former reaction proceeds via a nucleophilic trans-allene attack on the (pi-allyl)palladium intermediate, whereas the latter involves a syn-allene insertion into the allyl-Pd bond of the same intermediate. The products from the carbocylization undergo stereoselective Diels-Alder reactions to give stereodefined polycyclic systems in high yields.


Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis.
We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.


Semisynthesis of phosphovariants of Smad2 reveals a substrate preference of the activated T beta RI kinase.
Transforming growth factor-beta (TGF-beta) signaling regulates a wide range of cellular processes. Aberrant TGF-beta signaling has been implicated in various disease states in humans. A key element in this signaling pathway is phosphorylation of R-Smads such as Smad2 at the last two serine residues of the C-terminal sequence CSSXS (residues 463-467 in Smad2) by the TbetaRI receptor kinase. Phosphorylation results in the release of the R-Smad from the membrane-anchored protein SARA, binding to the co-mediator protein Smad4, translocation into the nucleus, and regulation of target gene expression. Expressed protein ligation was used to probe the contribution of the individual phosphate groups to Smad2 oligomerization and phosphorylation by TbetaRI. Phosphorylation at both positions was required to generate a stable homotrimer; however, the driving force for Smad2 self-association is provided by pSer465. Additionally, SARA was found to modulate the self-association of partially phosphorylated Smad2, which suggests an added role for this protein in preventing premature release of a monophosphorylated substrate from the receptor complex. In related studies, prephosphorylation of Smad2 at Ser465 was found to significantly increase the rate of phosphorylation at Ser467, suggesting that there may be specific recognition determinants within the kinase for the monophosphorylated intermediate. This information was exploited to design an improved peptide substrate for TbetaRI, which may prove valuable in the design of inhibitors of the TGF-beta pathway.


A diet enriched with curcumin impairs newly acquired and reactivated fear memories.
Curcumin, a yellow-pigment compound found in the popular Indian spice turmeric (Curcuma longa), has been extensively investigated for its anti-inflammatory, chemopreventative, and antidepressant properties. Here, we examined the efficacy of dietary curcumin at impairing the consolidation and reconsolidation of a Pavlovian fear memory, a widely studied animal model of traumatic memory formation in posttraumatic stress disorder (PTSD). We show that a diet enriched with 1.5% curcumin prevents the training-related elevation in the expression of the immediate early genes (IEGs) Arc/Arg3.1 and Egr-1 in the lateral amygdala (LA) and impairs the 'consolidation' of an auditory Pavlovian fear memory; short-term memory (STM) is intact, whereas long-term memory (LTM) is significantly impaired. Next, we show that dietary curcumin impairs the 'reconsolidation' of a recently formed auditory Pavlovian fear memory; fear memory retrieval (reactivation) and postreactivation (PR)-STM are intact, whereas PR-LTM is significantly impaired. Additional experiments revealed that dietary curcumin is also effective at impairing the reconsolidation of an older, well-consolidated fear memory. Furthermore, we observed that fear memories that fail to reconsolidate under the influence of dietary curcumin are impaired in an enduring manner; unlike extinguished fear memories, they are not subject to reinstatement or renewal. Collectively, our findings indicate that a diet enriched with curcumin is capable of impairing fear memory consolidation and reconsolidation processes, findings that may have important clinical implications for the treatment of disorders such as PTSD that are characterized by unusually strong and persistently reactivated fear memories.


Multifunctional cellulase enzymes are ancestral in Polyneoptera.
Many hemimetabolous insects produce their own cellulase enzymes from the glycoside hydrolase family 9, first observed in termites and cockroaches. Phasmatodea have multiple cellulases, some of which are multifunctional and can degrade xylan or xyloglucan. To discover when these abilities evolved, we identified cellulases from the Polyneoptera sampled by the 1000 Insect Transcriptome and Evolution (1KITE) project, including all cockroach and termite transcriptomes. We hoped to identify what role enzyme substrate specificities had in the evolution of dietary specification, such as leaf-feeding or wood-feeding. Putative cellulases were identified from the transcriptomes and analysed phylogenetically. All cellulases were amplified from an exemplar set of Polyneoptera species using rapid amplification of cDNA ends PCR and heterologously expressed in an insect cell line, then tested against different polysaccharides for their digestive abilities. We identified several multifunctional xyloglucanolytic enzymes across Polyneoptera, plus a large group of cellulase-like enzymes found in nearly all insect orders with no discernible digestive ability. Multifunctional xylanolytic cellulases remain unique to Phasmatodea. The presence or absence of multifunctional enzymes does not impact dietary specification, but rather having multiple, multifunctional cellulase genes is an ancestral state for Polyneoptera and possibly Insecta. The prevalence of multifunctional cellulases in other animals demands further investigation.


Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT).
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.


Implementation of a new 'community' laboratory CD4 service in a rural health district in South Africa extends laboratory services and substantially improves local reporting turnaround time.
The CD4 integrated service delivery model (ITSDM) provides for reasonable access to pathology services across South Africa (SA) by offering three new service tiers that extend services into remote, under-serviced areas. ITSDM identified Pixley ka Seme as such an under-serviced district. To address the poor service delivery in this area, a new ITSDM community (tier 3) laboratory was established in De Aar, SA. Laboratory performance and turnaround time (TAT) were monitored post implementation to assess the impact on local service delivery. Using the National Health Laboratory Service Corporate Data Warehouse, CD4 data were extracted for the period April 2012-July 2013 (n=11,964). Total mean TAT (in hours) was calculated and pre-analytical and analytical components assessed. Ongoing testing volumes, as well as external quality assessment performance across ten trials, were used to indicate post-implementation success. Data were analysed using Stata 12. Prior to the implementation of CD4 testing at De Aar, the total mean TAT was 20.5 hours. This fell to 8.2 hours post implementation, predominantly as a result of a lower pre-analytical mean TAT reducing from a mean of 18.9 to 1.8 hours. The analytical testing TAT remained unchanged after implementation and monthly test volumes increased by up to 20%. External quality assessment indicated adequate performance. Although subjective, questionnaires sent to facilities reported improved service delivery. Establishing CD4 testing in a remote community laboratory substantially reduces overall TAT. Additional community CD4 laboratories should be established in under-serviced areas, especially where laboratory infrastructure is already in place.


Urine Flow Dynamics Through Prostatic Urethra With Tubular Organ Modeling Using Endoscopic Imagery.
Voiding dysfunction is common in the aged male population. However, the obstruction mechanism in the lower urinary tract and critical points for obstruction remains uncertain. The aim of this paper was to develop a system to investigate the relationship between voiding dysfunction and alteration of the shape of the prostatic urethra by processing endoscopic video images of the urethra and analyzing the fluid dynamics of the urine stream. A panoramic image of the prostatic urethra was generated from cystourethroscopic video images. A virtual 3-D model of the urethra was constructed using the luminance values in the image. Fluid dynamics using the constructed model was then calculated assuming a static urethra and maximum urine flow rate. Cystourethroscopic videos from 11 patients with benign prostatic hyperplasia were recorded around administration of an alpha-1 adrenoceptor antagonist. The calculated pressure loss through the prostatic urethra in each model corresponded to the prostatic volume, and the improvements of the pressure loss after treatment correlated to the conventional clinical indices. As shown by the proposed method, the shape of the prostatic urethra affects the transporting urine fluid energy, and this paper implies a possible method for detecting critical lesions responsible for voiding dysfunction. The proposed method provides critical information about deformation of the prostatic urethra on voiding function. Detailed differences in the various types of relaxants for the lower urinary tract could be estimated.


Conjugate momentum estimate using non-linear dynamic model of the sit-to-stand correlates well with accelerometric surface data.
The purpose of this study was the development of a non-linear double inverted constrained pendulum model for the analysis of the movement of sit-to-stand (STS) transition. Ten able-bodied subjects perform five trials in their natural speed. Kinematics, kinetics as well as body worn accelerometer data were collected during the STS task using optoelectronic motion capture, force plate and inertial measurement unit, respectively. The conjugate momentum for the whole body which includes linear and angular motion correlates well with the accelerometric surface spanned by the accelerometer data. The partitioning of the conjugate momentum indicates a clear coordination between upper and lower limb after seat-off period. Moreover, the normalization procedure indicates a clear minimal and somehow invariant threshold value of the conjugate momentum to approximately 0.3 (body mass×body length) to perform the sit-to-stand for able-bodied subject. This threshold correlates well with the data obtained from accelerometeric index. The proposed accelerometric index is relevant to assess STS performance and to detect failed STS in clinics and outside a laboratory for patients with reduced mobility.


Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish.
Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.


Accumulation, selection and covariation of amino acids in sieve tube sap of tansy (Tanacetum vulgare) and castor bean (Ricinus communis): evidence for the function of a basic amino acid transporter and the absence of a γ-amino butyric acid transporter.
Sieve tube sap was obtained from Tanacetum by aphid stylectomy and from Ricinus after apical bud decapitation. The amino acids in sieve tube sap were analyzed and compared with those from leaves. Arginine and lysine accumulated in the sieve tube sap of Tanacetum more than 10-fold compared to the leaf extracts and they were, together with asparagine and serine, preferably selected into the sieve tube sap, whereas glycine, methionine/tryptophan and γ-amino butyric acid were partially or completely excluded. The two basic amino acids also showed a close covariation in sieve tube sap. The acidic amino acids also grouped together, but antagonistic to the other amino acids. The accumulation ratios between sieve tube sap and leaf extracts were smaller in Ricinus than in Tanacetum. Arginine, histidine, lysine and glutamine were enriched and preferentially loaded into the phloem, together with isoleucine and valine. In contrast, glycine and methionine/tryptophan were partially and γ-amino butyric acid almost completely excluded from sieve tube sap. The covariation analysis grouped arginine together with several neutral amino acids. The acidic amino acids were loaded under competition with neutral amino acids. It is concluded from comparison with the substrate specificities of already characterized plant amino acid transporters, that an AtCAT1-like transporter functions in phloem loading of basic amino acids, whereas a transporter like AtGAT1 is absent in phloem. Although Tanacetum and Ricinus have different minor vein architecture, their phloem loading specificities for amino acids are relatively similar.


Cell mediated immune responses following revaccination with an influenza A/H5N1 vaccine.
The study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses. Adults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus. PBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results. CMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine.


Is there evidence for potential harm of electronic cigarette use in pregnancy?
Use of electronic cigarettes (e-cigarettes) and other nicotine containing products is increasing among women of reproductive age. The short- and long-term effects of these products on both mother and fetus are unknown. Because e-cigarettes are nicotine delivery systems, we sought to conduct a comprehensive review of the effects of nicotine on the fetus. In utero nicotine exposure in animal models is associated with adverse effects for the offspring lung, cardiovascular system and brain. In the lung, this included reduced surface area, weight, and volume, as well as emphysema-like lesions. In adulthood, exposed offspring demonstrate elevated blood pressure and increased perivascular adipose tissue. In the brain, exposure alters offspring serotonergic, dopaminergic, and norepinephrine networks, which in turn are associated with behavioral and cognitive impairments. We also review current data on the lack of efficacy of nicotine replacement therapy in pregnant women, and highlight different nicotine containing products such as snuff, snus, and hookah. We conclude that no amount of nicotine is known to be safe during pregnancy, and studies specifically addressing this risk are crucial and an imminent public health issue.


Predictive factors of catheter-related bloodstream infection in patients receiving home parenteral nutrition.
The aim of this study was to determine the incidence and predictive factors of catheter-related bloodstream infections (CRBSIs) acquired through a central venous catheter for delivery of home parenteral nutrition (HPN) therapy among a patient population in Thailand. This retrospective review was conducted with adult patients with intestinal failure who received HPN from October 2002 to April 2014, at Ramathibodi Home Parenteral and Enteral Nutrition Referral Center in Bangkok. Seventy-two patients (45.8% male, mean age 56.2 ± 15.7 y) were included in the analysis. Incidence of CRBSIs was 1.47 per 1000 catheter days. Over the 12-y period, there were 21 CRBSIs among 10 patients. There were 26 pathogens isolated from these CRBSIs, mostly coagulase-negative staphylococci. Univariate Poisson regression analysis revealed that the incidence rate ratio of CRBSIs was significantly higher in patients who used an implanted port (compared with tunneled catheter), alcohol-based povidone-iodine solution as disinfectant (compared with 2% chlorhexidine gluconate in 70% isopropyl alcohol), cyclic HPN infusion (compared with continuous HPN), and hospital-based compound HPN formulations (compared with 3-in-1 commercial formulations). Furthermore, longer duration of HPN (>250 d) was associated with CRBSIs. Multivariate analysis revealed that longer duration of HPN, cyclic HPN, and hospital-based compound HPN were significantly associated with CRBSIs. CRBSI is a significant complication in patients receiving long-term HPN. Individualized therapy with a multidisciplinary team in centers with HPN management expertise is required. Careful selection of the catheter type and HPN formulation for each patient is necessary to best meet patient requirements and minimize HPN-related complications. Strict compliance by patients and caregivers with evidence-based instructions together with supervision by well-trained HPN providers is the most effective strategy to prevent CRBSIs.


Application of random amplified polymorphic DNA analysis to differentiate strains of Salmonella enteritidis.
A random amplified polymorphic DNA (RAPD) fingerprinting method has been developed to differentiate Salmonella enteritidis isolates. A total of 65 arbitrary primers were screened with S. enteritidis isolates of different phage types. This allowed selection of a panel of primers capable of detecting DNA polymorphisms among S. enteritidis isolates. This panel was used to examine a panel of 29 isolates of S. enteritidis which had been previously characterized by other subtyping methods, including phage typing (PT) (n = 7), ribotyping (RT) (n = 13), and pulsed-field gel electrophoresis (PFGE). Applied collectively, these three methods resolved the collection into 20 different subtypes. However, by the RAPD fingerprinting method alone, 14 RAPD subtypes were revealed. Eight isolates of S. enteritidis phage type 8 that failed to be discriminated by other typing methods (PT, RT, and PFGE) were resolved into three different subtypes by RAPD analysis. In contrast, isolates that were derived from the same sources were not differentiated by any of the subtyping methods employed, including PT, RT, PFGE, and RAPD analysis. This RAPD approach to S. enteritidis subtyping provided more discriminatory power than did any of several other subtyping methods applied individually. Once the challenging step of primer identification was accomplished, determinations of the appropriate concentrations of arbitrary primer, DNA template, and MG2+ ion were also necessary for optimal discriminatory power. The bacterial DNA used in this RAPD protocol was obtained by boiling the bacterial sample. This simple procedure yielded DNA that produced fingerprint patterns as consistent as those obtained from phenol-chloroform-extracted DNA. Clearly, when appropriately constituted primer sets are identified and employed, RAPD analysis provides a simple, rapid, and powerful subtyping method for S. enteritidis.


Comfort experience in palliative care: a phenomenological study.
Palliative care aims to provide maximum comfort to the patient. However it is unknown what factors facilitate or hinder the experience of comfort, from the perspective of inpatients of palliative care units. This lack of knowledge hinders the development of comfort interventions adjusted to these patients. The aim of this research is to describe the comfort and discomfort experienced by inpatients at palliative care units. A phenomenological descriptive study was undertaken. Ten inpatients were recruited from a Spanish palliative care unit and seven from a Portuguese palliative care unit. Data were collected using individual interviews and analysed following the method of Giorgi. Four themes reflect the essence of the lived experience: The Palliative Care as a response to the patient's needs with advanced disease, attempt to naturalize advanced disease, confrontation with their own vulnerability, openness to the spiritual dimension. Informants revealed that they experience comfort through humanized care, differentiated environment, symptomatic control, hope and relationships. The discomfort emerges from the losses and powerlessness against their situation. Even if such findings may seem intuitive, documenting them is essential because it invites us to reflect on our convictions about what it means to be comfortable for these patients, and allows incorporating this information in the design of focused interventions to maximize the comfort experience.


Linear population allocation by bistable switches in response to transient stimulation.
Many cellular decision processes, including proliferation, differentiation, and phenotypic switching, are controlled by bistable signaling networks. In response to transient or intermediate input signals, these networks allocate a population fraction to each of two distinct states (e.g. OFF and ON). While extensive studies have been carried out to analyze various bistable networks, they are primarily focused on responses of bistable networks to sustained input signals. In this work, we investigate the response characteristics of bistable networks to transient signals, using both theoretical analysis and numerical simulation. We find that bistable systems exhibit a common property: for input signals with short durations, the fraction of switching cells increases linearly with the signal duration, allowing the population to integrate transient signals to tune its response. We propose that this allocation algorithm can be an optimal response strategy for certain cellular decisions in which excessive switching results in lower population fitness.


RING finger and WD repeat domain 3 (RFWD3) associates with replication protein A (RPA) and facilitates RPA-mediated DNA damage response.
DNA damage response is crucial for maintaining genomic integrity and preventing cancer by coordinating the activation of checkpoints and the repair of damaged DNA. Central to DNA damage response are the two checkpoint kinases ATM and ATR that phosphorylate a wide range of substrates. RING finger and WD repeat domain 3 (RFWD3) was initially identified as a substrate of ATM/ATR from a proteomic screen. Subsequent studies showed that RFWD3 is an E3 ubiquitin ligase that ubiquitinates p53 in vitro and positively regulates p53 levels in response to DNA damage. We report here that RFWD3 associates with replication protein A (RPA), a single-stranded DNA-binding protein that plays essential roles in DNA replication, recombination, and repair. Binding of RPA to single-stranded DNA (ssDNA), which is generated by DNA damage and repair, is essential for the recruitment of DNA repair factors to damaged sites and the activation of checkpoint signaling. We show that RFWD3 is physically associated with RPA and rapidly localizes to sites of DNA damage in a RPA-dependent manner. In vitro experiments suggest that the C terminus of RFWD3, which encompass the coiled-coil domain and the WD40 domain, is necessary for binding to RPA. Furthermore, DNA damage-induced phosphorylation of RPA and RFWD3 is dependent upon each other. Consequently, loss of RFWD3 results in the persistent foci of DNA damage marker γH2AX and the repair protein Rad51 in damaged cells. These findings suggest that RFWD3 is recruited to sites of DNA damage and facilitates RPA-mediated DNA damage signaling and repair.


Sodium-bicarbonated mineral water decreases aldosterone levels without affecting urinary excretion of bone minerals.
AIM To assess in healthy postmenopausal women the influence of consuming sodium-bicarbonated mineral water on postprandial evolution of serum aldosterone and urinary electrolyte excretion. Eighteen postmenopausal women consumed 500 ml of two sodium-bicarbonated mineral waters (sodium-bicarbonated mineral water 1 and sodium-bicarbonated mineral water 2) and a low-mineral water with a standard meal. Postprandial blood samples were taken at 60, 120, 240, 360 and 420 min and aldosterone concentrations were measured. Postprandial urinary minerals were determined. Urinary and total mineral excretion and urinary mineral concentrations did not differ except for sodium concentration, which was significantly higher with sodium-bicarbonated mineral water 1 than with low-mineral water (P = 0.005). There was a time effect (P = 0.003) on the aldosterone concentration. At 120 min, aldosterone concentrations were lower with sodium-bicarbonated mineral water 1 (P = 0.021) and sodium-bicarbonated mineral water 2 (P = 0.030) compared with low-mineral water. Drinking a sodium-rich bicarbonated mineral water with a meal increases urinary sodium concentration excretion without changes in the excretion of potassium and bone minerals.


Sleep and behavior problems in school-aged children.
The primary purposes of the present study were to survey the prevalence of sleep problems in school-aged children and to examine these associations with parental perception of sleep problems, medical history, and childhood psychopathology. Sleep and medical history questionnaires and the Child Behavior Checklist were administered to the parents of 472 children between ages 4 and 12 years receiving routine pediatric care from urban, rural, and suburban pediatric practices. Although sleep problems were reported for 10.8% of the sample during the past 6 months, less than one half of the parents who identified sleep problems reported that they had discussed sleep with their child's pediatrician. The best predictor of current sleep problems was a history of sleep problems before age 2 years. Sleep problems such as snoring, tiredness during the day, and taking excessive time to fall asleep were very common, occurring at least 1 night per week in over 20% of the total sample. Factor analysis of the sleep problems questionnaire resulted in 5 sleep problem factors that accounted for 58.7% of the variance. Specific sleep problem factors include: parasomnias, enuresis/gags, tiredness, noisy sleep, and insomnia. Sleep problem factor scores were differentially associated with medical history variables and measures of childhood psychopathology. Children rated highly on parasomnias were more likely to have frequent falls and to display pica. Parasomnias and noisy sleep were inversely associated with socioeconomic status (SES). Children from lower SES families were rated higher on these factors than children from higher SES families. Enuresis/gags was the only sleep problem factor associated with age. Younger children scored higher on this factor. Duration of naps was highly correlated with age and with bed times during the week and weekends. As expected, younger children were more likely to nap for longer periods and to have earlier bed times. In addition, higher tiredness factor scores were associated with napping and with later bed times during the week and weekend. Boys were much more likely than were girls to have higher scores on enuresis/gags, and higher enuresis/gags scores were associated with an increased prevalence of trauma and falls. Bed times were not associated with any other sleep problem factor score. Children rated highly on tiredness were more likely to have a history of hospitalizations. Tiredness factor scores were strongly associated with the sleep practice of sharing a bed but not with sharing a room. Sharing a room was not associated with any sleep problem factor score. High scores on noisy sleep were associated with allergies, falls frequently, and with sharing a bed. Children with high scores on the insomnias were also more likely to display an increased prevalence of allergies. Parental perception of global sleep problems was surprisingly common in school-aged children receiving routine pediatric care. Parental reports of their children's sleep problems may be a red flag for specific sleep problems and psychiatric, social, or medical problems. Sleep problems should be queried about during pediatric visits for school-aged children.


Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants.
Lithium augmentation, the most studied augmentation strategy for depression, has not been evaluated in patients with a history of non-response to multiple antidepressants. The objective of this study was to assess the efficacy of lithium augmentation for patients with a history of treatment resistant depression who also failed a prospective trial of nortriptyline. We enrolled 92 subjects with treatment resistant depression. Treatment resistance was defined by at least one, but no more than five, adequate trials of antidepressants during the current episode. Subjects were treated with nortriptyline (NT) for 6 weeks. Those subjects who tolerated NT for 6 weeks and whose depression did not respond (n=35) were randomized to receive either lithium (n=18) or placebo (N=17) augmentation of nortriptyline for an additional 6 weeks. Response was defined as an equal to or greater than 50% decrease in HAM-D-17 scores. After 6 weeks of double-blind augmentation, 12.5 % of subjects responded to lithium and 20.0% to placebo. Our results revealed no significant difference between lithium and placebo augmentation. While lithium augmentation seems to be useful in depression refractory to a single medication in some studies, our data suggest limited usefulness of this option for patients refractory to multiple treatments. More definitive data await the outcome of the NIMH Sequential Treatment Alternatives to Relieve Depression (STAR*D) study.


Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.
Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages. We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm). EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β<high school = 1.05 (0.09, 2.01) vs college graduates] and FFCWS [GEEs: β<high school = 0.62 (0.00, 1.24)]. We found stronger associations for some paternal education categories among White adults (for GEE, βsome college = -1.39 (-2.41, -0.38)], men (βsome college = -1.76 (-3.16, -0.35)] and women [β<high school = 1.77 (0.42, 3.11)]. These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.


Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine.
A DNA vaccine against the hepatitis B virus (HBV) was evaluated for safety and induction of immune responses in 12 healthy, hepatitis-naïve human volunteers using the needle-free PowderJect system to deliver gold particles coated with DNA directly into cells of the skin. Three groups of four volunteers received three administrations of DNA encoding the surface antigen of HBV at one of the three dose levels (1, 2, or 4 microg). The vaccine was safe and well tolerated, causing only transient and mild to moderate responses at the site of administration. HBV-specific antibody and both CD4+ and CD8+ T cell responses were measured before and after each immunization. All the volunteers developed protective antibody responses of at least 10 mIU/ml. In volunteers who were positive for the HLA class I A2 allele, the vaccine also induced antigen-specific CD8+ T cells that bound HLA-A2/HBsAg(335-343) tetramers, secreted IFN-gamma, and lysed target cells presenting a hepatitis B surface antigen (HBsAg) CTL epitope. Enumeration of HBsAg-specific T cells producing cytokine indicated preferential induction of a Type 1 T helper cell response. These results provide the first demonstration of a DNA vaccine inducing protective antibody titers and both humoral and cell-mediated immune responses in humans.


The early development of self-injurious behaviour: evaluating the role of social reinforcement.
The potential role of social reinforcement in the development of self-injury has not yet been subjected to empirical analysis. In this 2-year prospective study, the pattern of social interactions related to the early presentation of self-injury were examined to identify a potential association with an increase in self-injury. The self-injurious behaviour and social contact with adults of 16 children with intellectual disability (ID) with self-injury of recent onset were observed at 3-month intervals over 2 years. Increase in self-injury over a 2-year period was positively correlated with a distribution of social contact relative to episodes of self-injury that is consistent with a mutual social reinforcement paradigm. When this paradigm was operative, self-injury was evoked under stable antecedent conditions over time but tended to evoke increasing levels of social interaction. These results support the hypothesis that increases in the frequency of early self-injury in children with ID may be determined by social reinforcement with implications for early intervention and proactive identification of children at risk for increases in self-injury.


Human enhancement and communication: on meaning and shared understanding.
Our technologies have enabled us to change both the world and our perceptions of the world, as well as to change ourselves and to find new ways to fulfil the human desire for improvement and for having new capacities. The debate around using technology for human enhancement has already raised many ethical concerns, however little research has been done in how human enhancement can affect human communication. The purpose of this paper is to explore whether some human enhancements could change our shared lifeworld so radically that human communication as we know it would not be possible any longer. After exploring the kinds of communication problems we are concerned with as well as mentioning some possible enhancement interventions that could bring about such problems, we will address some of the ethical implications that follow from these potential communication problems. We argue that because of the role that communication plays in human society, this issue deserves attention.


Disruptions to schistosomiasis programmes due to COVID-19: an analysis of potential impact and mitigation strategies.
The 2030 goal for schistosomiasis is elimination as a public health problem (EPHP), with mass drug administration (MDA) of praziquantel to school-age children (SAC) as a central pillar of the strategy. However, due to coronavirus disease 2019, many mass treatment campaigns for schistosomiasis have been halted, with uncertain implications for the programmes. We use mathematical modelling to explore how postponement of MDA and various mitigation strategies affect achievement of the EPHP goal for Schistosoma mansoni and S. haematobium. For both S. mansoni and S. haematobium in moderate- and some high-prevalence settings, the disruption may delay the goal by up to 2 y. In some high-prevalence settings, EPHP is not achievable with current strategies and so the disruption will not impact this. Here, increasing SAC coverage and treating adults can achieve the goal. The impact of MDA disruption and the appropriate mitigation strategy varies according to the baseline prevalence prior to treatment, the burden of infection in adults and the stage of the programme. Schistosomiasis MDA programmes in medium- and high-prevalence areas should restart as soon as is feasible and mitigation strategies may be required in some settings.


Regression analysis of spatial data.
Many of the most interesting questions ecologists ask lead to analyses of spatial data. Yet, perhaps confused by the large number of statistical models and fitting methods available, many ecologists seem to believe this is best left to specialists. Here, we describe the issues that need consideration when analysing spatial data and illustrate these using simulation studies. Our comparative analysis involves using methods including generalized least squares, spatial filters, wavelet revised models, conditional autoregressive models and generalized additive mixed models to estimate regression coefficients from synthetic but realistic data sets, including some which violate standard regression assumptions. We assess the performance of each method using two measures and using statistical error rates for model selection. Methods that performed well included generalized least squares family of models and a Bayesian implementation of the conditional auto-regressive model. Ordinary least squares also performed adequately in the absence of model selection, but had poorly controlled Type I error rates and so did not show the improvements in performance under model selection when using the above methods. Removing large-scale spatial trends in the response led to poor performance. These are empirical results; hence extrapolation of these findings to other situations should be performed cautiously. Nevertheless, our simulation-based approach provides much stronger evidence for comparative analysis than assessments based on single or small numbers of data sets, and should be considered a necessary foundation for statements of this type in future.


Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents.
This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.