Changing Criminal Attitudes Among Incarcerated Offenders: Initial Examination of a Structured Treatment Program.
The present study investigated the effect of a criminal attitude treatment program to changes on measured criminal attitudes and postprogram recidivism. The criminal attitude program (CAP) is a standardized therapeutic curriculum consisting of 15 modules offering 44 hr of therapeutic time. It was delivered by trained facilitators to a total of 113 male offenders incarcerated in one of five state correctional institutions. Pretreatment and posttreatment comparisons were made on standardized measures of criminal attitudes, response bias, and motivation for lifestyle changes. Results found statistically significant lower criminal attitudes at posttreatment that were unaffected by response bias. There were also increases in motivation for lifestyle changes, but these did not reach statistical significance. Fifty-seven participants were released into the community following the program and were eligible for recidivism analyses. Comparisons between participants who completed the CAP and those who did not complete the CAP revealed 7% lower rearrest among CAP completers. Although preliminary, these results indicate that the CAP had a positive effect on changes to criminal attitudes and recidivism. The findings are discussed in terms of conceptual and practical considerations in the assessment and treatment of criminal attitudes among offenders.


Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (SR 4233).
P450 reductase (NADPH:cytochrome P450 reductase, EC 22.214.171.124) is known to be important in the reductive activation of the benzotriazene-di-N-oxide tirapazamine (SR 4233). Using a panel of six human breast adenocarcinoma cell lines we have examined the relationship between P450 reductase activity and sensitivity to tirapazamine. The toxicity of tirapazamine was found to correlate strongly with P450 reductase activity following an acute (3 h) exposure under hypoxic conditions, the drug being most toxic in the cell lines with the highest P450 reductase activity. A similar correlation was also observed following a chronic (96 h) exposure to the drug in air but not following acute (3 h) exposure in air. We have also determined the ability of lysates prepared from the cell lines to metabolise tirapazamine to its two-electron reduced product, SR 4317, under hypoxic conditions using NADPH as an electron donor. The rate of SR 4317 formation was found to correlate both with P450 reductase activity and with sensitivity to tirapazamine, the highest rates of SR 4317 formation being associated with the highest levels of P450 reductase activity and the greatest sensitivity to the drug. These findings indicate a major role for P450 reductase in determining the hypoxic toxicity of tirapazamine in breast tumour cell lines.


Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors.
Endocrine pancreatic tumors are neuroendocrine neoplasms with malignant potential and give rise to varied clinical syndromes due to excessive secretion of multiple hormones. In this study 22 endocrine pancreatic tumors and 11 carcinoid tumors were examined for the expression of CD44 using a monoclonal antibody. CD44 gene activity of 11 endocrine pancreatic tumor tissues and five carcinoid tumor tissues was also studied by amplifying messenger RNA with the polymerase chain reaction followed by electrophoresis and blot hybridization. Strong immunoreactivity was detected on all gastrinomas examined (P < 0.001), and in two non-functioning endocrine pancreatic tumors. Such immunoreactivity was not observed in other subtypes of endocrine pancreatic tumors. In the normal human pancreas, the acinar portion and ductal epithelial cells stained strongly positive but pancreatic islet cells did not show any significant immunostaining. Furthermore, in endocrine pancreatic tumors with metastatic disease, CD44-positive tumors had a tendency to metastasize to lymph nodes (P = 0.005), as compared with CD44-negative tumors which were locally invasive or metastasized to the liver. Although, in this limited material and short follow-up, we were not able to show any statistical significance, patients with CD44-negative endocrine pancreatic tumors had prolonged survival time compared with patients with CD44-positive tumors (73% versus 59% at 5 years; P = 0.7). Of 10 carcinoid tumors examined, all three foregut carcinoids and one midgut carcinoid stained strongly positive, whereas all other midgut carcinoids were negative. Analysis of CD44 splice variants showed that in all five gastrinomas there was overproduction of alternatively spliced larger molecular variants as compared with other types of endocrine pancreatic tumors and carcinoid tumors. The band pattern from one case of carcinoid tumor with a fulminant clinical course was similar to that of gastrinomas, whereas other carcinoid tumors expressed the epithelial form of CD44. The earlier identified splice variants which confer metastatic behavior on a pancreatic tumor cell line were not expressed in neuroendocrine tumors. Our data indicate that CD44 expression in endocrine pancreatic tumors correlates with the ability to give rise to lymph node metastases and may play a vital role in determining the fate of metastasizing cells. Moreover, because gastrin is not detectable in the normal human pancreas, the pancreatic ductal cell positivity for CD44 strengthened the ductal origin concept of gastrinomas. The band pattern of CD44 splice variants suggests that the previously described splice variants conferring metastatic behavior do not accompany metastatic activity of neuroendocrine tumors.


Prospective Validation of Sedation Scale Scores That Identify Light Sedation: A Pilot Study.
Intensive care unit (ICU) sedation guidelines recommend targeting a light sedation level, but light sedation has no accepted definition, and inconsistent levels have been proposed. To determine Sedation-Agitation Scale and Richmond Agitation-Sedation Scale scores that best describe patients' ability to follow voice commands. This prospective, observational pilot study enrolled a convenience sample of ICU patients receiving mechanical ventilation. Pairs of trained investigators evaluated scores on the Sedation-Agitation Scale and Richmond Agitation-Sedation Scale and ability to follow commands before and up to 2 hours after sedation lightening in a blind, independent, simultaneous fashion. Positive predictive values (PPVs) and likelihood ratios (LRs) of Sedation-Agitation Scale and Richmond Agitation-Sedation Scale scores associated with light sedation (ability to follow at least 3 commands) were calculated. Ninety-six assessments (50 before and 46 after lightening of sedation) were performed in medical ICU patients. Scores best associated with ability to follow at least 3 commands were Sedation-Agitation Scale score of 4 (PPV, 0.88; 95% CI, 0.70-0.98; LR, 14.0) and Richmond Agitation-Sedation Scale score of -1 (PPV, 0.81; 95% CI, 0.61-0.93; LR, 10.7), superior to previously recommended thresholds of Sedation-Agitation Scale score of 3 (PPV, 0.62; 95% CI, 0.48-0.75; LR, 3.1) and Richmond Agitation-Sedation Scale score of -3 (PPV, 0.52; 95% CI, 0.39-0.64; LR, 2.0). The level of sedation most associated with the ability to follow commands appears higher than previously recommended. Further study is needed regarding the effects of sedation level on ICU patients' ability to follow commands and assessment of delirium, pain, and patient preferences.


Regulation of human basophil adhesion to endothelium under flow conditions: Different very late antigen 4 regulation on umbilical cord blood-derived and peripheral blood basophils.
Although soluble mediators released by basophils in tissue sites contribute to the chronic injury that occurs in hypersensitivity diseases, only limited information is available about how circulating basophils are recruited to tissues. In particular, the interaction of basophils with endothelium under conditions that mimic physiologic flow has not been explored. We sought to identify adhesion molecules regulating the attachment of human basophils to IL-4-activated human umbilical vein endothelial cells (HUVECs) under flow conditions. A parallel-plate flow chamber and blocking mAbs were used to define the adhesion molecules involved in the interactions of peripheral blood basophils (PBBs) and cord blood-derived basophils (CBDBs) with IL-4-activated HUVECs and with Chinese hamster ovary (CHO) cell transfectants expressing specific adhesion molecules. A fluorescent ligand specific for very late antigen 4 (VLA-4) was used to directly examine the VLA-4 affinity state of basophils. Flowing PBBs and CBDBs attached to activated HUVECs and to CHO cells expressing P- or E-selectin. However, only CBDBs attached to vascular cell adhesion molecule 1 (VCAM-1)-transfected CHO cells under flow conditions. The attachment of CBDBs to CHO cells was blocked by mAbs directed against E-selectin, P-selectin, and VCAM-1, whereas attachment of PBBs was blocked by E-selectin and P-selectin mAbs. Activating VLA-4 with Mn(2+) on PBBs resulted in adhesion to the VCAM-1-transfected CHO cells, indicating that VLA-4 activity on PBBs can be regulated, at least in part, through affinity changes. The Mn(2+)-induced upregulation of basophil VLA-4 affinity was demonstrated directly by using a fluorescent ligand for VLA-4 and flow cytometry. The interaction of human CBDBs and PBBs with endothelium under flow conditions is mediated in part by both P- and E-selectin. VLA-4 additionally contributes to the adhesion of flowing CBDBs. However, the affinity of VLA-4 is too low to support the adhesion under flow conditions of unstimulated PBBs.


Occurrence and correlates of fatigue in psoriatic arthritis.
To determine the relationship between fatigue and disease-related and psychosocial variables in psoriatic arthritis (PsA). 499 patients attending the University of Toronto PsA Clinic were administered the modified fatigue severity scale (mFSS). At the time of mFSS administration, clinical and laboratory measures of disease activity and damage were recorded. Linear regression models were used to examine the cross-sectional relationship between disease-related and psychosocial variables and mFSS scores. At least moderate fatigue occurred in 49.5% of patients and severe fatigue in 28.7%. Univariately the vast majority of variables were significantly associated with mFSS scores. The final multivariate model was composed of female sex, the medical outcome survey short form 36 (SF-36) pain and mental health scales, the number of fibromyalgia tender points, the health assessment questionnaire (HAQ) and "ever used" methotrexate, and explained 54.5% of the variation in mFSS scores. The SF-36 mental health scale played the largest role in the multivariate model, uniquely accounting for 6.6% of the variation in the fatigue severity scale. The disease-related factors significant at the univariate level did not achieve statistical significance in the context of HAQ and pain measures. Fatigue is a common symptom in PsA, and is associated, in a multivariate model, with pain, female sex, physical functional disability, medication status and psychological distress. Fatigue appears to provide some information that does not overlap with the core set of outcome domains in PsA.


Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein.
Calcium-binding proteins dubbed KChIPs favour surface expression and modulate inactivation gating of neuronal and cardiac A-type Kv4 channels. To investigate their mechanism of action, Kv4.1 or Kv4.3 were expressed in Xenopus laevis oocytes, either alone or together with KChIP1, and the K+ currents were recorded using the whole-oocyte voltage-clamp and patch-clamp methods. KChIP1 similarly remodels gating of both channels. At positive voltages, KChIP1 slows the early phase of the development of macroscopic inactivation. By contrast, the late phase is accelerated, which allows complete inactivation in < 500 ms. Thus, superimposed traces from control and KChIP1-remodelled currents crossover. KChIP1 also accelerates closed-state inactivation and recovery from inactivation (3- to 5-fold change). The latter effect is dominating and, consequently, the prepulse inactivation curves exhibit depolarizing shifts (DeltaV = 4-12 mV). More favourable closed-state inactivation may also contribute to the overall faster inactivation at positive voltages because Kv4 channels significantly inactivate from the preopen closed state. KChIP1 favours this pathway further by accelerating channel closing. The peak G-V curves are modestly leftward shifted in the presence of KChIP1, but the apparent 'threshold' voltage of current activation remains unaltered. Single Kv4.1 channels exhibited multiple conductance levels that ranged between 1.8 and 5.6 pS in the absence of KChIP1 and between 1.9 and 5.3 pS in its presence. Thus, changes in unitary conductance do not contribute to current upregulation by KChIP1. An allosteric kinetic model explains the kinetic changes by assuming that KChIP1 mainly impairs open-state inactivation, favours channel closing and lowers the energy barrier of closed-state inactivation.


Gas-phase vibrational spectroscopy of triphenylamine: the effect of charge on structure and spectra.
The effect of ionization by oxidation and protonation on the structure and IR spectrum of isolated, gas-phase triphenylamine (TPA) has been investigated by infrared multiple photon dissociation (IRMPD) spectroscopy in the fingerprint range from 600 cm-1 to 1800 cm-1 using an infrared free electron laser. IR spectra calculated using density functional theory (DFT) convincingly reproduce the experimental data. Spectral and structural differences are identified among neutral TPA, TPA˙+ and protonated TPA and qualitatively related to effects of resonance delocalization. As a consequence of electron delocalization, computed structural parameters for TPA remain virtually unchanged upon removal of an electron. Nonetheless, CC and CN stretching vibrations in the IR spectra of TPA˙+ undergo a red shift of up to 52 cm-1 as compared to those in TPA. Since ionization also strongly influences the relative band intensities, a vibrational projection analysis was used to correlate vibrational modes of TPA with those of TPA˙+. The experimental IR spectrum of gas-phase protonated TPA indicates that protonation occurs on the nitrogen atom, despite delocalization of the lone electron pair. Upon protonation, the structure changes from the nearly planar geometry to a near-tetrahedral configuration.


A study on scalable representations for evolutionary optimization of ground structures.
This paper presents a comparative study of two indirect solution representations, a generative and an ontogenic one, on a set of well-known 2D truss design problems. The generative representation encodes the parameters of a trusses design as a mapping from a 2D space. The ontogenic representation encodes truss design parameters as a local truss transformation iterated several times, starting from a trivial initial truss. Both representations are tested with a naive evolution strategy based optimization scheme, as well as the state of the art HyperNEAT approach. We focus both on the best objective value obtained and the computational cost to reach a given level of optimality. The study shows that the two solution representations behave very differently. For experimental settings with equal complexity, with the same optimization scheme and settings, the generative representation provides results which are far from optimal, whereas the ontogenic representation delivers near-optimal solutions. The ontogenic representation is also much less computationally expensive than a direct representation until very close to the global optimum. The study questions the scalability of the generative representations, while the results for the ontogenic representation display much better scalability.


Spectroscopic characterization of mononitrosyl complexes in heme--nonheme diiron centers within the myoglobin scaffold (Fe(B)Mbs): relevance to denitrifying NO reductase.
Denitrifying NO reductases are evolutionarily related to the superfamily of heme--copper terminal oxidases. These transmembrane protein complexes utilize a heme-nonheme diiron center to reduce two NO molecules to N(2)O. To understand this reaction, the diiron site has been modeled using sperm whale myoglobin as a scaffold and mutating distal residues Leu-29 and Phe-43 to histidines and Val-68 to a glutamic acid to create a nonheme Fe(B) site. The impact of incorporation of metal ions at this engineered site on the reaction of the ferrous heme with one NO was examined by UV-vis absorption, EPR, resonance Raman, and FTIR spectroscopies. UV--vis absorption and resonance Raman spectra demonstrate that the first NO molecule binds to the ferrous heme, but while the apoproteins and Cu(I)- or Zn(II)-loaded proteins show characteristic EPR signatures of S = 1/2 six-coordinate heme {FeNO}(7) species that can be observed at liquid nitrogen temperature, the Fe(II)-loaded proteins are EPR silent at ≥30 K. Vibrational modes from the heme [Fe-N-O] unit are identified in the RR and FTIR spectra using (15)NO and (15)N(18)O. The apo and Cu(I)-bound proteins exhibit ν(FeNO) and ν(NO) that are only marginally distinct from those reported for native myoglobin. However, binding of Fe(II) at the Fe(B) site shifts the heme ν(FeNO) by 17 cm(-1) and the ν(NO) by -50 cm(-1) to 1549 cm(-1). This low ν(NO) is without precedent for a six-coordinate heme {FeNO}(7) species and suggests that the NO group adopts a strong nitroxyl character stabilized by electrostatic interaction with the nearby nonheme Fe(II). Detection of a similarly low ν(NO) in the Zn(II)-loaded protein supports this interpretation.


Persistence of the decline in the diagnosis of schizophrenia among first admissions to Scottish hospitals from 1969 to 1988.
Age-standardised rates were calculated for first admissions to hospital in Scotland with ICD-9 diagnoses of schizophrenia, affective psychoses, paranoid psychoses, reactive psychoses and depressive neuroses (ICD-9 295, 296, 297, 298 and 300.4) for the period 1969-88. First-admission rates for schizophrenia declined by an average of 3.3% per year in males and 4.4% per year in females over the period. The first-admission rate in males in 1988 was 8.4/100,000 (57% of 1969 rate) and in females was 4.8/100,000 (43% of 1969 rate). Rates for depressive neuroses, affective psychoses, reactive psychoses and combined psychoses also fell. Rates for mania rose, as did those for paranoid states in males. The decrease in first-admission rates is likely to reflect a true decrease in the incidence of schizophrenia over the period. The decline was unlikely to be accounted for by diagnostic change because there was no reciprocal increase in any other diagnosis sufficient to account for the change, and the rates for combined psychoses also decreased. There was evidence that rates for schizophrenia declined to a greater extent in younger age groups, especially in females. This could imply the presence of a birth cohort effect.


Health care workers' perspectives about disclosure to HIV-infected children; cross-sectional survey of health facilities in Gauteng and Mpumalanga provinces, South Africa.
The perspectives and practices of health care workers (HCWs) regarding disclosure to HIV-infected children have not been adequately investigated ten years after the roll-out of pediatrics antiretroviral therapy (ART). The aim of the study was to examine the opinions of HCWs about disclosure to HIV-infected children and determine their role in disclosure to children accessing ART in health centers in South Africa. This was a cross-sectional survey using a semi-structured questionnaire among HCWs in ART centers at three hospitals and 48 primary health facilities in two provinces in South Africa. Of the 206 HCWs, 140 (68.2%) were nurses, 44 (21.5%) were lay counsellors, and 4 (2%) were doctors. The majority (n = 183, 89.3%) felt that disclosure benefits children and they should be told about their HIV status. Over half (n = 93, 51.4%) recommended 11-18 years as the appropriate age to disclose. Half (n = 99, 48.5%) said that caregivers should take the lead to disclose, 87 (42.7%) said that disclosure is a shared responsibility of caregivers and HCWs, and 18 (8.8%) said HCWs should lead disclosure. HCWs perceived their role as that of preparing the caregiver for disclosure and the child to understand the disease. However, the lack of guidelines and training on disclosure counselling for children affects their ability to fully participate in disclosure to children. There is a need to adopt the World Health Organizations' disclosure guidelines for children and adapt them to the local cultural and community contexts and train HCWs to guide, support, and assist caregivers in their disclosure to HIV-infected children.


Hyponatraemia and its prognosis in acute heart failure is related to right ventricular dysfunction.
Hyponatraemia is a well-known predictor of clinical outcomes in heart failure (HF). However, the mechanism remains poorly understood. Previous reports suggest that hyponatraemia is related to right HF. We sought to evaluate the association between right ventricular (RV) dysfunction and hyponatraemia, and the impact of this relationship on the prognosis of patients with acute heart failure (AHF). This is a nested case-control study of the Korean Acute Heart Failure registry. Among 2935 AHF patients enrolled prospectively and consecutively at four tertiary hospitals in Korea from 2011 to 2014, 116 patients with severe persistent hyponatraemia, defined as serum sodium level <130 mmol/L at admission and <135 mmol/L before discharge, were matched with 232 controls, based on propensity scores for hyponatraemia. RV function was assessed with fractional area change (FAC) by echocardiography. RV dysfunction (FAC <35%) was more prevalent in patients with severe persistent hyponatraemia than in those without (81.0% vs 33.6%, p<0.001). Hyponatraemia was strongly associated with RV dysfunction (adjusted OR 8.00, 95% CI 4.50 to 14.22, p<0.001), but not with left ventricular dysfunction (adjusted OR 1.21, 95% CI 0.74 to 1.50, p=0.308). RV dysfunction was an independent predictor of all-cause mortality, after adjustment for hyponatraemia (adjusted HR 2.20, 95% CI 1.53 to 3.15, p<0.001), while hyponatraemia was not (adjusted HR 1.33, 95% CI 0.94 to 1.87, p=0.108). In patients with AHF, hyponatraemia was more common with RV dysfunction. RV dysfunction, rather than hyponatraemia, was more significantly related with patients' prognosis. Thus, the utility of RV dysfunction instead of hyponatraemia per se should be considered in HF risk models. Korean Acute Heart Failure registry NCT01389843; Results.


New strategies for the treatment and prevention of primary headache disorders.
The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists. Neuromodulation approaches employing noninvasive or implantable devices also show promise for treating primary headache disorders. Noninvasive treatments, such as transcranial magnetic stimulation and transcutaneous peripheral nerve stimulation, are delivered by devices that patients can self-administer. Implantable devices targeting the occipital nerves, sphenopalatine ganglion or high cervical spinal cord are placed using percutaneous and/or surgical procedures, and are powered either wirelessly or by surgically implanted batteries. These new and emerging treatments have the potential to address unmet patient needs and reduce headache-associated disability.


Harnessing Social Media to Explore Youth Social Withdrawal in Three Major Cities in China: Cross-Sectional Web Survey.
Socially withdrawn youth belong to an emerging subgroup of youth who are not in employment, education, or training and who have limited social interaction intention and opportunities. The use of the internet and social media is expected to be an alternative and feasible way to reach this group of young people because of their reclusive nature. The aim of this study was to explore the possibility of using various social media platforms to investigate the existence of the phenomenon of youth social withdrawal in 3 major cities in China. A cross-sectional open Web survey was conducted from October 2015 to May 2016 to identify and reach socially withdrawn youth in 3 metropolitan cities in China: Beijing, Shanghai, and Shenzhen. To advertise the survey, 3 social media platforms were used: Weibo, WeChat, and Wandianba, a social networking gaming website. In total, 137 participants completed the survey, among whom 13 (9.5%) were identified as belonging to the withdrawal group, 7 (5.1%) to the asocial group, and 9 (6.6%) to the hikikomori group (both withdrawn and asocial for more than 3 months). The cost of recruitment via Weibo was US $7.27 per participant. Several social media platforms in China are viable and inexpensive tools to reach socially withdrawn youth, and internet platforms that specialize in a certain culture or type of entertainment appeared to be more effective in reaching socially withdrawn youth.


Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy.
Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca(2+) sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca(2+)-binding EF hands. Ca(2+) stores are refilled through a process called store-operated Ca(2+) entry (SOCE). Upon Ca(2+)-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca(2+) entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca(2+) sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca(2+) level in TAM cells and a dysregulation of intracellular Ca(2+) homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function.


Namaste care delivered by caregivers of community-dwelling older adults with moderate to advanced dementia: A mixed methods study protocol.
The aim of this study is to adapt and evaluate the feasibility, acceptability, and preliminary effectiveness of a multisensory, psychosocial intervention called Namaste Care delivered by family and friend caregivers of community-dwelling older adults with moderate to advanced dementia. A multiphase mixed methods design combining quantitative and qualitative methods will be used. This study is composed of two phases. Phase 1 is guided by a qualitative description approach. Small group workshop sessions with 8-10 caregivers of community-dwelling older adults with moderate to advanced dementia will be conducted to adapt Namaste Care. In Phase 2, 10-20 caregivers will receive training and implement the adapted Namaste Care approach at home. A one group, before-after design will be used to evaluate feasibility, acceptability and preliminary effectiveness of the approach over 3 months. Feasibility will be assessed using quantitative measures and acceptability will be explored using qualitative methods. Outcomes to evaluate preliminary effectiveness include quality of life (QoL), positive perceptions of caregiving, self-efficacy, and caregiver burden. There are currently few skill-building interventions that can be delivered by caregivers of people with moderate to advanced dementia at home. Caregivers should be involved in developing programs to enhance program relevance. This research will be the first to explore the feasibility of implementing the Namaste Care approach at home by caregivers. Study results will provide important information about the feasibility and preliminary effects of an adapted form of Namaste Care. This program has the potential to improve the QoL of caregivers and may prevent hospitalization or long-term care placement of older persons with moderate to advanced dementia. The revised Namaste Care program supports building the skills of caregivers so that their needs and the needs of older persons with dementia living at home are being addressed.


Reactive oxygen species in BCR-ABL1-expressing cells - relevance to chronic myeloid leukemia.
Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be engaged in CML progression and TKI-resistance and warrant further study.


Structural and functional complexity of the genomic region controlling AK-toxin biosynthesis and pathogenicity in the Japanese pear pathotype of Alternaria alternata.
The Japanese pear pathotype of Alternaria alternata produces host-specific AK-toxin and causes black spot of Japanese pear. Previously, a cosmid clone, pcAKT-1, was isolated that contains two genes, AKT1 and AKT2, within a 5.0-kb region required for AK-toxin biosynthesis. The wild-type strain has multiple, nonfunctional copies of these genes. In the present study, two additional genes, AKTR-1 and AKT3-1, downstream of AKT2 were identified. Transformation of the wild type with AKTR-1- and AKT3-1-targeting vectors produced toxin-deficient (Tox-), nonpathogenic mutants. DNA gel blot analysis, however, demonstrated that the fragments targeted in Tox- mutants were different from those containing AKTR-1 and AKT3-1 on the transforming vectors. A cosmid clone, pcAKT-2, containing the targeted DNA was isolated and shown to carry two genes, AKTR-2 and AKT3-2, with high similarity to AKTR-1 and AKT3-1, respectively. Transcripts from not only AKTR-2 and AKT3-2 but also AKTR-1 and AKT3-1 were found in the wild type. DNA gel blot analysis with pulsed-field gel electrophoresis showed that AKT1, AKT2, AKT3, and AKTR and their homologues are on a single chromosome. These results indicate the structural and functional complexity of the genomic region controlling AK-toxin biosynthesis.


Maternal and fetal single nucleotide polymorphisms in the epoxide hydrolase and gluthatione S-transferase P1 genes are not associated with pre-eclampsia in the Coloured population of the Western Cape, South Africa.
Oxidative stress is thought to play an important role in the pathophysiology of pre-eclampsia. A defect in certain enzymes responsible for detoxification may cause prolonged exposure to reactive by-products and contribute to maternal endothelial as well as placental damage. Two polymorphisms affecting the function of the biotransformation enzymes epoxide hydrolase and glutathione S-transferase P1 were shown previously to be associated with pre-eclampsia in a Dutch population. The aim of this study was to determine if these two polymorphisms (maternal or fetal) contribute to pre-eclampsia in an anthropologically distinct population (the Western Cape region of South Africa) with a high incidence of the disease. Genomic DNA of mother - infant pairs with severe pre-eclampsia (n = 144), a population control group (n = 156) and control mother - infant pairs with uncomplicated pregnancy outcome (n = 45) were analysed for the EPHX and GSTP1 polymorphisms by polymerase chain reaction amplification and restriction enzyme digestion. Each polymorphism had a similar distribution in case and control subjects (mother and infant). The Val105/Val105 genotype of GSTP1 occurred at a higher frequency than reported for other populations. Neither maternal nor fetal EPHX Tyr113His and GSTP1 Ile105Val polymorphisms appear to contribute significantly to the pathophysiology of pre-eclampsia in the Coloured population of the Western Cape region of South Africa.


Over-expression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancer cells.
Ubiquitin carboxy terminal hydrolase-L1 (UCH-L1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Previous research showed that UCH-L1 was expressed in mouse retinal cells and testicular germ cells, and its function was associated with apoptosis. But it is still unclear whether UCH-L1 is concerned with apoptosis in tumor cells. In order to clarify the role of UCH-L1 in tumor cells, multi-drug resistance (MDR) human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We transfected pcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively. Using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, western blot, Hoechst 33258 staining assay and flow cytometry, we found that over-expression of UCH-L1 in MCF7 cells induced apoptosis. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Moreover, to explore the mechanism underling these observations, we further investigated the expression of phospho-Akt and its downstream signal phospho-IkB-alpha and other signal molecules including Fas, Fas-L, Trail, DR4, DR5, Bax, cytochrome C, active caspase-3, phospho-p53, phospho-Mdm-2, Bcl-2, Bcl-xL, p21 and p27. The results indicated that the process of apoptosis triggered by UCH-L1 is, at least in part, probably through Phosphoinositide 3-kinase (PI3K)/Akt signal pathway. Our findings suggest that modulating the ubiquitination and deubiquitination pathway could be a novel method for tumor therapy.


Relations between infant neurobehavioral performance and cognitive outcome in very low birth weight preterm infants.
The predictive utility of three aspects of neonatal neurobehavioral performance was examined in 144 very low birth weight (< 1500 g) preterms who were followed until 6 years of age. Visual-following and auditory-orienting composites derived from the Einstein Neonatal Neurobehavioral Assessment Scale were modestly related to the Mental Developmental Index (MDI) and IQ scores at several ages, whereas the active motility composite was only related to MDI scores at 1 year of age (corrected). Infants who showed deviant performance on both visual following and auditory orienting composites had significantly lower cognitive test scores at 1 and 6 years of age and were more likely to be classified as subaverage at 6 years of age (IQ < 85). Group differences were independent of both neonatal health status and motor scores and were not due to the performance of children with severe sensory impairments. These findings suggest that visual following and auditory orienting measured in the neonatal period can offer a useful way of indexing initial capacities.


Principles and progress in ultrafast multidimensional nuclear magnetic resonance.
Multidimensional acquisitions play a central role in the progress and applications of nuclear magnetic resonance (NMR) spectroscopy. Such experiments have been collected traditionally as an array of one-dimensional scans, with suitably incremented delay parameters that encode along independent temporal domains the nD spectral distribution being sought. During the past few years, an ultrafast approach to nD NMR has been introduced that is capable of delivering any type of multidimensional spectrum in a single transient. This method operates by departing from the canonical nD NMR scheme and by replacing its temporal encoding with a series of spatial manipulations derived from magnetic resonance imaging. The present survey introduces the main principles of this subsecond approach to spectroscopy, focusing on the applications that have hitherto been demonstrated for single-scan two-dimensional NMR in different areas of chemistry.


Asia-Pacific consensus on the management of gastroesophageal reflux disease: update.
Since the publication of the Asia-Pacific GERD consensus in 2004, more data concerning the epidemiology and management of gastroesophageal reflux disease (GERD) have emerged. An evidence based review and update was needed. A multidisciplinary group developed consensus statements using the Delphi approach. Relevant data were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. GERD is increasing in frequency in Asia. Risk factors include older age, male sex, race, family history, higher socioeconomic status, increased body mass index, and smoking. Symptomatic response to a proton pump inhibitor (PPI) test is diagnostic in patients with typical symptoms if alarm symptoms are absent. A negative pH study off therapy excludes GERD if a PPI test fails. The role for narrow band imaging, capsule endoscopy, and wireless pH monitoring has not yet been undefined. Diagnostic strategies in Asia must consider coexistent gastric cancer and peptic ulcer. Weight loss and elevation of head of bed improve reflux symptoms. PPIs are the most effective medical treatment. On-demand therapy is appropriate for nonerosive reflux disease (NERD) patients. Patients with chronic cough, laryngitis, and typical GERD symptoms should be offered twice daily PPI therapy after excluding non-GERD etiologies. Fundoplication could be offered to GERD patients when an experienced surgeon is available. Endoscopic treatment of GERD should not be offered outside clinical trials. Further studies are needed to clarify the role of newer diagnostic modalities and endoscopic therapy. Diagnostic strategies for GERD in Asia must consider coexistent gastric cancer and peptic ulcer. PPIs remain the cornerstone of therapy.


Markov State Models and tICA Reveal a Nonnative Folding Nucleus in Simulations of NuG2.
After reanalyzing simulations of NuG2-a designed mutant of protein G-generated by Lindorff-Larsen et al. with time structure-based independent components analysis and Markov state models as well as performing 1.5 ms of additional sampling on Folding@home, we found an intermediate with a register-shift in one of the β-sheets that was visited along a minor folding pathway. The minor folding pathway was initiated by the register-shifted sheet, which is composed of solely nonnative contacts, suggesting that for some peptides, nonnative contacts can lead to productive folding events. To confirm this experimentally, we suggest a mutational strategy for stabilizing the register shift, as well as an infrared experiment that could observe the nonnative folding nucleus.


Chlamydia trachomatis IgG seroprevalence in the general population of the Netherlands in 1996 and in 2007: differential changes by gender and age.
Chlamydia trachomatis (CT) reporting rates from sexually transmitted infection clinics and general practitioners have shown a rising trend in the Netherlands. It is unknown to what extent this reflects increased CT transmission or improved case finding. To achieve more insight into the CT epidemic, we explored the CT IgG seroprevalence (a marker of past CT infection) in the general population of the Netherlands in 1996 and in 2007. From two population-based studies in 1996 and 2007, serum samples, demographic and sexual behaviour outcomes were examined, including 1246 men and 1930 women aged 15-39 years. Serum CT IgG antibodies were analysed using the Medac CT IgG ELISA test. Multivariate logistic regression analyses explored the seroprevalence and determinants over time. The CT IgG seroprevalence was higher in women than in men (10% vs 6%). Among women aged 25-39 years the seroprevalence was lower in 2007 (9%) than in 1996 (14%; adjusted OR (aOR) 0.6, 95% CI 0.4 to 0.8). There was no statistical evidence of a difference in seroprevalence within birth cohorts. Factors associated with seropositivity were male gender (aOR 0.4, 95% CI 0.3 to 0.7), a self-reported history of CT infection (aOR 5.1, 95% CI 2.6 to 10.0), age 25-39 years (aOR 1.7, 95% CI 1.1 to 2.7), non-Western ethnicity (aOR 2.2, 95% CI 1.4 to 3.3) and ≥ 2 recent sexual partners (aOR 2.2, 95% CI 1.3 to 3.5). Between 1996 and 2007 the proportion of individuals in the general population with CT IgG antibodies was lower among women aged 25-39 years, but remained similar among younger women and men.


Development of a skill mix and study planning tool for research teams.
There are various tools available in acute and primary care settings to support decision making about safe-staffing levels. Calculating safe staffing levels is about more than just the number of people on duty. It must reflect skill mix and tasks, and this is more complex outside traditional nursing roles. It is essential that research nurses, who work in multidisciplinary teams collecting the evidence that underpins safe and effective healthcare, are equipped to practise safely, but staffing level tools do not take their unique roles into account. This article describes University Hospitals Bristol Research Work Plan Tool (BRIS-TOOL), developed to enable research managers to identify skill mix in their teams and support effective study planning. It also discusses how the tool accurately reflects research teams' productivity. Finally, the article suggests that the tool can be used to profile research posts, illustrate the breadth of work undertaken in these posts, inform study design and help clinical colleagues to understand research roles better.


Standardizing estimates of the Plasmodium falciparum parasite rate.
The Plasmodium falciparum parasite rate (PfPR) is a commonly reported index of malaria transmission intensity. PfPR rises after birth to a plateau before declining in older children and adults. Studies of populations with different age ranges generally report average PfPR, so age is an important source of heterogeneity in reported PfPR data. This confounds simple comparisons of PfPR surveys conducted at different times or places. Several algorithms for standardizing PfPR were developed using 21 studies that stratify in detail PfPR by age. An additional 121 studies were found that recorded PfPR from the same population over at least two different age ranges; these paired estimates were used to evaluate these algorithms. The best algorithm was judged to be the one that described most of the variance when converting the PfPR pairs from one age-range to another. The analysis suggests that the relationship between PfPR and age is predictable across the observed range of malaria endemicity. PfPR reaches a peak after about two years and remains fairly constant in older children until age ten before declining throughout adolescence and adulthood. The PfPR pairs were poorly correlated; using one to predict the other would explain only 5% of the total variance. By contrast, the PfPR predicted by the best algorithm explained 72% of the variance. The PfPR in older children is useful for standardization because it has good biological, epidemiological and statistical properties. It is also historically consistent with the classical categories of hypoendemic, mesoendemic and hyperendemic malaria. This algorithm provides a reliable method for standardizing PfPR for the purposes of comparing studies and mapping malaria endemicity. The scripts for doing so are freely available to all.


Predicting the time needed for environmental systematic reviews and systematic maps.
Systematic reviews (SRs) and systematic mapping aim to maximize transparency and comprehensiveness while minimizing subjectivity and bias. These are time-consuming and complex tasks, so SRs are considered resource intensive, but published estimates of systematic-review resource requirements are largely anecdotal. We analyzed all Collaboration for Environmental Evidence (CEE) SRs (n = 66) and maps (n = 20) published from 2012 to 2017 to estimate the average number of articles retained at each review stage. We also surveyed 33 experienced systematic reviewers to collate information on the rate at which those stages could be completed. In combination, these data showed that the average CEE SR takes an estimated 164 d (full-time equivalent) (SD 23), and the average CEE systematic map (SM) (excluding critical appraisal) takes 211 d (SD 53). While screening titles and abstracts is widely considered time-consuming, metadata extraction and critical appraisal took as long or longer to complete, especially for SMs. Given information about the planned methods and evidence base, we created a software tool that predicts time requirements of a SR or map with evidence-based defaults as a starting point. Our results shed light on the most time-consuming stages of the SR and mapping processes, will inform review planning, and can direct innovation to streamline processes. Future predictions of effort required to complete SRs and maps could be improved if authors provide more details on methods and results.


Biparental mucus feeding: a unique example of parental care in an Amazonian cichlid.
Vertebrates display a wide variety of parental care behaviours, including the guarding of offspring pre and post nutritional independence as well as the direct provision of nutrients during the early development period. The Amazonian cichlid Symphysodon spp. (discus fish) is unusual among fish species, in that both parents provide offspring with mucus secretions to feed from after hatching. This extensive provision of care, which can last up to a month, imposes a physiological demand on both parents and gives rise to conflict between the parent and offspring. Here, we investigated the relationship between parents and offspring during a breeding cycle, determining both mucus composition (total protein, cortisol, immunoglobulin, and Na(+), K(+) and Ca(2+) concentrations) and the behavioural dynamics of the parent-offspring relationship. Over the course of a breeding cycle, a significant increase in offspring bite rate was recorded, with a concomitant increase in the frequency of turns the male and female parent took at caring for their young. A peak in mucus antibody provision was seen as offspring reached the free-swimming stage, suggesting a role analogous to colostrum provision in mammals. Mucus protein content was lowest during the second and third weeks of free swimming, and a weaning period, similar to that seen in mammalian parental care, occurred when the offspring had been free swimming for ∼3 weeks. In many ways, the parental behaviour of discus fish is more similar to mammalian and avian parental care than other fish species, and represents an exciting aquatic model for studying the parent-offspring conflict.


Mobile Digital Education for Health Professions: Systematic Review and Meta-Analysis by the Digital Health Education Collaboration.
There is a pressing need to implement efficient and cost-effective training to address the worldwide shortage of health professionals. Mobile digital education (mLearning) has been mooted as a potential solution to increase the delivery of health professions education as it offers the opportunity for wide access at low cost and flexibility with the portability of mobile devices. To better inform policy making, we need to determine the effectiveness of mLearning. The primary objective of this review was to evaluate the effectiveness of mLearning interventions for delivering health professions education in terms of learners' knowledge, skills, attitudes, and satisfaction. We performed a systematic review of the effectiveness of mLearning in health professions education using standard Cochrane methodology. We searched 7 major bibliographic databases from January 1990 to August 2017 and included randomized controlled trials (RCTs) or cluster RCTs. A total of 29 studies, including 3175 learners, met the inclusion criteria. A total of 25 studies were RCTs and 4 were cluster RCTs. Interventions comprised tablet or smartphone apps, personal digital assistants, basic mobile phones, iPods, and Moving Picture Experts Group-1 audio layer 3 player devices to deliver learning content. A total of 20 studies assessed knowledge (n=2469) and compared mLearning or blended learning to traditional learning or another form of digital education. The pooled estimate of studies favored mLearning over traditional learning for knowledge (standardized mean difference [SMD]=0.43, 95% CI 0.05-0.80, N=11 studies, low-quality evidence). There was no difference between blended learning and traditional learning for knowledge (SMD=0.20, 95% CI -0.47 to 0.86, N=6 studies, low-quality evidence). A total of 14 studies assessed skills (n=1097) and compared mLearning or blended learning to traditional learning or another form of digital education. The pooled estimate of studies favored mLearning (SMD=1.12, 95% CI 0.56-1.69, N=5 studies, moderate quality evidence) and blended learning (SMD=1.06, 95% CI 0.09-2.03, N=7 studies, low-quality evidence) over traditional learning for skills. A total of 5 and 4 studies assessed attitudes (n=440) and satisfaction (n=327), respectively, with inconclusive findings reported for each outcome. The risk of bias was judged as high in 16 studies. The evidence base suggests that mLearning is as effective as traditional learning or possibly more so. Although acknowledging the heterogeneity among the studies, this synthesis provides encouraging early evidence to strengthen efforts aimed at expanding health professions education using mobile devices in order to help tackle the global shortage of health professionals.


PTEN knockout prostate cancer as a model for experimental immunotherapy.
Testing immunotherapeutic strategies for prostate cancer has been impeded by the lack of relevant tumor models in immunocompetent animals. This opportunity is now provided by the recent development of prostate specific PTEN knockout mice, which show spontaneous development of true adenocarcinoma arising from prostate epithelium and more faithfully recapitulate the human disease than any previous model. We investigated the feasibility of using tumor cells derived from this model to test tumor vaccination and adoptive immunotherapeutic strategies for prostate cancer. PTEN-CaP8 adenocarcinoma cells derived from the biallelic PTEN knockout prostate cancer model were used to vaccinate nontumor bearing litter mates. Tumor specific effector cells were generated from splenocytes of vaccinated mice by mixed lymphocyte-tumor reactions, and antiproliferative effects and cytokine generation were examined in vitro. The effect of vaccination or adoptive immunotherapy on luciferase marked PTEN-CaP8 subcutaneous tumors was monitored by tumor volumetric measurements and noninvasive bioluminescence imaging. Vaccination of litter mate mice with irradiated PTEN-CaP8 cells showed a significant prophylactic effect against the subsequent tumor challenge. Effector cells harvested from vaccinated litter mates showed significant interferon-gamma secretion upon co-incubation with PTEN-CaP8 target cells and they were capable of efficient target cell growth inhibition in vitro. Intratumor adoptive transfer of effector cells resulted in significant growth inhibition of preestablished prostate tumors in vivo. The PTEN knockout model serves as a highly useful model in which to investigate tumor cell vaccination and adoptive immunotherapeutic strategies in the context of true adenocarcinoma of the prostate. This model should accelerate efforts to develop effective immunotherapies for human prostate cancer.


Mechanisms of translational regulation by a human eIF5-mimic protein.
The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNA(i)(Met) ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function.


The economic payoffs of integrated malaria control in the Zambian copperbelt between 1930 and 1950.
It has long been suggested that malaria is delaying the economic development of countries that are most severely affected by the disease. Several studies have documented the economic consequences of malaria at the household level, primarily in communities engaged in subsistence farming. A missing element is the appraisal of the economic impact of malaria on the industrial and service sectors that will probably become the backbone of many developing economies. We estimate the economic effects of integrated malaria control implemented during the colonial period and sustained for 20 years in four copper mining communities of the former Northern Rhodesia (now Zambia). Integrated malaria control was characterized by strong emphasis on environmental management, while part of the mining communities also benefited from rapid diagnosis and treatment and the use of bednets. The programmes were highly successful as an estimated 14,122 deaths, 517,284 malaria attacks and 942,347 work shift losses were averted. Overall, 127,226 disability adjusted life years (DALYs) were averted per 3-year incremental period. The cumulative costs of malaria control interventions were 11,169,472 US dollars (in 1995 US dollars). Because the control programmes were so effective, the mining companies attracted a large reservoir of migrant labourers and sustained healthy work forces. The programmes averted an estimated 796,622 US dollars in direct treatment costs and 5,678,745 US dollars in indirect costs as a result of reduced work absenteeism. Within a few years of programme initiation, Northern Rhodesia became the leading copper producer in Africa, and mining generated the dominant share of national income. Copper production and revenues, which increased dramatically during malaria control interventions, amounted to the equivalent of 7.1 billion US dollars (in 1995 US dollars). Integrated malaria control in copper mining communities was a sound investment. It had payoff for public and occupational health, generally, and without it copper extraction and social and economic development would have been impossible.


The Effect of Change in Intraocular Pressure on Choroidal Structure in Glaucomatous Eyes.
Choroidal thickness increases linearly with intraocular pressure (IOP) lowering. We studied the relationship between the change in size of the choroidal vasculature and IOP lowering after glaucoma procedures. Thirty eyes of twenty-nine patients were examined pre- and postoperatively for up to 6 months with standard clinical assessment, enhanced depth imaging spectral-domain optical coherence tomography (OCT), and axial length measurement. Each enhanced depth imaging spectral-domain OCT image was analyzed using three separate methods to determine the choroidal thickness, choroidal vessel thickness, choroidal interstitial thickness, large choroidal vessel layer thickness, medium choroidal vessel layer thickness, and light-dark ratio. Bivariate linear regression analysis was completed with largest change in IOP as the independent variable. The dependent variables included choroidal thickness, choroidal vessel thickness, and choroidal interstitial thickness, at the largest change in IOP. Multivariable regression analysis using a generalized estimating equation to account for multiple measurements per eye was also completed. Mean choroidal vessel thickness increases 1.5 μm for every 1 mm Hg decrease in IOP (P < 0.0001; 95% confidence interval [CI], 0.8, 2.1) and choroidal interstitial thickness increases 1.3 μm for every 1 mm Hg change in IOP (P < 0.0001; 95% CI, 0.8, 1.8). There was no significant association between change in IOP and change in large choroidal vessel layer temporally (P = 0.13), nasally (P = 0.20), or subfoveally (P = 0.18). There was also no association between IOP and the light-dark ratio (P = 0.16). The increase in choroidal thickness at lower IOP is associated with approximately equal increases in its intravascular and extravascular compartments.


Nanotopography featured polycaprolactone/polyethyleneoxide microfibers modulate endothelial cell response.
Among many physical properties, surface nanotopography has been found to strongly affect cell adhesion, migration and other functions. Accurate biological interpretation requires the nanotopography to be presented in a three-dimensional (3D) micro-environment. Herein, immiscible blends of polycaprolactone (PCL)/polyethyleneoxide (PEO) were electrospun into a grounded coagulation bath, resulting in macroporous microfibers with nanotopography featured surfaces. Variations in PCL/PEO ratios enabled tunable surface nanotopographic structures, from longitudinal submicron grooves to transverse nano-lamellae. Chemical composition, crystallinity and quantitative nanomechanical analysis confirmed that the interplay of the two semi-crystalline immiscible polymers and the pairing of miscible solvents/non-solvents in both the electrospinning solution and the bath solution were critical for the formation of the secondary structure. It was found that the nanotopography features promoted the proliferation of human umbilical vein endothelial cells (HUVECs) compared with their smooth film counterparts. An analysis of the cell adhesion related markers, vinculin and phosphorylated focal adhesion kinase (pFAK), further revealed that the nanotopographies enhanced the nascent adhesion complex formation compared with smooth PCL fibers, even in the scaffolds with a high PEO content, which is often considered as a non-adhesive material.


Plasmodium berghei Kinesin-5 Associates With the Spindle Apparatus During Cell Division and Is Important for Efficient Production of Infectious Sporozoites.
Kinesin-5 motors play essential roles in spindle apparatus assembly during cell division, by generating forces to establish and maintain the spindle bipolarity essential for proper chromosome segregation. Kinesin-5 is largely conserved structurally and functionally in model eukaryotes, but its role is unknown in the Plasmodium parasite, an evolutionarily divergent organism with several atypical features of both mitotic and meiotic cell division. We have investigated the function and subcellular location of kinesin-5 during cell division throughout the Plasmodium berghei life cycle. Deletion of kinesin-5 had little visible effect at any proliferative stage except sporozoite production in oocysts, resulting in a significant decrease in the number of motile sporozoites in mosquito salivary glands, which were able to infect a new vertebrate host. Live-cell imaging showed kinesin-5-GFP located on the spindle and at spindle poles during both atypical mitosis and meiosis. Fixed-cell immunofluorescence assays revealed kinesin-5 co-localized with α-tubulin and centrin-2 and a partial overlap with kinetochore marker NDC80 during early blood stage schizogony. Dual-color live-cell imaging showed that kinesin-5 is closely associated with NDC80 during male gametogony, but not with kinesin-8B, a marker of the basal body and axonemes of the forming flagella. Treatment of gametocytes with microtubule-specific inhibitors confirmed kinesin-5 association with nuclear spindles and not cytoplasmic axonemal microtubules. Altogether, our results demonstrate that kinesin-5 is associated with the spindle apparatus, expressed in proliferating parasite stages, and important for efficient production of infectious sporozoites.


Developing an interprofessional care plan for an older adult woman with breast cancer: from multiple voices to a shared vision.
Interprofessional collaboration is central to quality patient care; however, little is known about developing interprofessional care plans, particularly in oncology. This article describes the development of an interprofessional care plan for an older adult woman with breast cancer. Two collaborative expert workshops were used; 15 clinical experts reviewed an online patient case and were asked to prepare a uniprofessional care plan. In workshop 1, participants worked from a draft interprofessional care plan, synthesized from the uniprofessional care plans by research associates, to arrive at consensus on an ideal interprofessional care plan. Using qualitative inductive content analysis of workshop transcripts, specific changes and overall key principles were identified and used to revise the draft plan. Based on these findings, a generalized interprofessional care plan/oncology model was developed. Revisions and proposed model were validated through consensus by participants during workshop 2. Participants highlighted the iterative, cyclical, and multilayered nature of patient care experiences; the importance of central patient profiles, which are contributed to and validated by all healthcare professionals; and the importance of assessing patient understanding. Participation of a patient representative provided an invaluable contribution. The process and model provide a unique framework for interprofessional care plan development in other settings and patient populations.


[Nursing Experience of Using Mirror Visual Feedback for a Schizophrenia Patient With Visual Hallucinations].
The aim of this paper was to describe the nursing application of mirror visual feedback in a patient suffering from long-term visual hallucinations. The intervention period was from May 15th to October 19th, 2015. Using the five facets of psychiatric nursing assessment, several health problems were observed, including disturbed sensory perceptions (prominent visual hallucinations) and poor self-care (e.g. limited abilities to self-bathe and put on clothing). Furthermore, "caregiver role strain" due to the related intense care burden was noted. After building up a therapeutic interpersonal relationship, the technique of brain plasticity and mirror visual feedback were performed using multiple nursing care methods in order to help the patient suppress her visual hallucinations by enhancing a different visual stimulus. We also taught her how to cope with visual hallucinations in a proper manner. The frequency and content of visual hallucinations were recorded to evaluate the effects of management. The therapeutic plan was formulated together with the patient in order to boost her self-confidence, and a behavior contract was implemented in order to improve her personal hygiene. In addition, psychoeducation on disease-related topics was provided to the patient's family, and they were encouraged to attend relevant therapeutic activities. As a result, her family became less passive and negative and more engaged in and positive about her future. The crisis of "caregiver role strain" was successfully resolved. The current experience is hoped to serve as a model for enhancing communication and cooperation between family and staff in similar medical settings.


Novel combined management approaches to patients with diabetes, chronic kidney disease and cardiovascular disease.
Most patients we care for today suffer from more than one chronic disease, and multimorbidity is a rapidly growing challenge. Concomitant cardiovascular disease, renal dysfunction and diabetes represent a large proportion of all patients in cardiology, nephrology and diabetology. These entities commonly overlap due to their negative effects on vascular function and an accelerated atherosclerosis progression. At the same time, a progressive subspecialisation has caused the cardiologist to treat 'only' the heart, nephrologists 'only' the kidneys and endocrinologists' 'only' diabetes. Studies and guidelines follow the same pattern. This often requires patients to visit specialists for each field, with a risk of both under-diagnosis and under-treatment. From the patient's perspective, there is a great need for coordination and facilitation of the care, not only to reduce disease progression but also to improve quality of life. Person-centred integrated clinics for patients with cardiovascular disease, renal dysfunction and diabetes are a promising approach for complex chronic disease management.


Perceptions of the family mealtime environment and adolescent mealtime behavior: do adults and adolescents agree?
The family mealtime environment has great potential to affect the eating behaviors of youth in the family. It is difficult to determine the important elements of a healthy mealtime environment because a valid assessment of the family environment is so difficult to obtain.The objective of this study is to examine the level of agreement between adult and adolescent perceptions of the family mealtime environment and adolescent mealtime behavior.A telephone survey was used to query adult and adolescent family members about how they perceive the family mealtime environment and the adolescent's mealtime behavior. A convenience sample of 282 adult/adolescent pairs from four schools in the Minneapolis/St. Paul area completed the telephone surveys. Frequencies of responses and the associations between the adult and adolescent responses are presented. Pearson correlations and regression were used to examine the level of association between adult and adolescent responses. Mixed-model regression was used for the continuous variables, and mixed-model logistic regression was used for the dichotomous variables. This study showed very little concordance between adolescent and adult responses. Only one question regarding arguments about eating during mealtime showed concordance. Adults and adolescents living in the same household seem to have different perceptions of the family mealtime environment and adolescent eating patterns. Researchers need to be aware of and concerned with the validity of the use of self-report for descriptions of family mealtime. They also need to be aware of the difference in adult and adolescent perceptions and consider these differences when designing messages for the family.


Alcohol production as an adaptive livelihood strategy for women farmers in Tanzania and its potential for unintended consequences on women's reproductive health.
Although women occupy a central position in agriculture in many developing countries, they face numerous constraints to achieving their full potential including unequal access to assets and limited decision-making authority. We explore the intersection of agricultural livelihoods, food and economic security, and women's sexual and reproductive health in Iringa Region, Tanzania. Our goal was to understand whether the benefits of supporting women in the agricultural sector might also extend to more distal outcomes, including sexual and reproductive health. Using the Sustainable Livelihoods Framework to guide data collection, we conducted 13 focus group discussions (FGD) with female (n = 11) and male farmers (n = 2) and 20 in-depth interviews with agricultural extension officers (n = 10) and village agro-dealers (n = 10). Despite providing the majority of agricultural labor, women have limited control over land and earned income and have little bargaining power. In response to these constraints, women adopt adaptive livelihood strategies, such as alcohol production, that allow them to retain control over income and support their households. However, women's central role in alcohol production, in concert with the ubiquitous nature of alcohol consumption, places them at risk by enhancing their vulnerability to unsafe or transactional sex. This represents a dangerous confluence of risk for female farmers, in which alcohol plays an important role in income generation and also facilitates high-risk sexual behavior. Alcohol production and consumption has the potential to both directly and indirectly place women at risk for undesirable sexual and reproductive health outcomes. Group formation, better access to finance, and engaging with agricultural extension officers were identified as potential interventions for supporting women farmers and challenging harmful gender norms. In addition, joint, multi-sectoral approaches from health and agriculture and alternative income-generating strategies for women might better address the complexities of achieving safe and sustainable livelihoods for women in this context.


Dietary α-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance.
Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin αIIbβ3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-α-converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders.


Hunter's technique without Hunter's rod.
Silicon rods initially advocated by Hunter have been widely used in two-stage flexor tendon reconstruction. Two-stage tendoplasty is an expensive procedure; with the addition of the high cost of rods, it is still more expensive. An experimental study investigated cheaper alternatives to silicon rods, but no clinical studies seem to have been reported so far. This study involved 17 patients undergoing two stage flexor tendon grafting. In all fingers, silicon urinary catheters were used as tendon prosthesis. The Wehbe et al modification of the Boyes and Stark classification was used for preoperative classification and Strickland formulation and Buck-Gramcko criteria for postoperative analysis. This clinical study showed that comparable clinical results and proper pseudosheaths for tendon grafting with similar histological and physical features can be obtained using a silicon urinary catheter which is fifty times less costly than Hunter's rod.


Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84.
Treatment with parathyroid hormone [PTH(1-84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n=8) or 100 microg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV/TV) measured by microcomputed tomography and histomorphometry was 45-48% higher in subjects treated with PTH(1-84) versus placebo, a result of higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intratrabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH(1-84)-treated subjects, primarily because of greater mineralizing surface. Osteoblast and osteoid surfaces were a nonsignificant 58% and 35%, respectively, higher with PTH(1-84) treatment. Osteoclast and eroded surface were unaffected by PTH(1-84). There were no effects of PTH(1-84) treatment on cortical thickness, or endocortical or periosteal BFR, but cortical porosity tended to be higher. Although cancellous BFR was lower at 24 than at 18 months, measures of cancellous and cortical bone structure were similar at both timepoints. The bone produced by PTH(1-84) had normal lamellar structure and mineralization with no abnormal histology. In conclusion, when compared with placebo, treatment of osteoporotic women with PTH(1-84) was associated with higher BV/TV and trabecular connectivity, with a more plate-like architecture, all consistent with the lower vertebral fracture incidence.


Biochemical and structural characterization of recombinant copper-metallothionein from Saccharomyces cerevisiae.
Methods were developed for large-scale purification of recombinant Cu-metallothionein (Cu-MT) for structural investigations and the determination of Cu-binding stoichiometry. Cu-MT of Saccharomyces cerevisiae overexpressed in Escherichia coli was purified using a procedure based on ion exchange and gel filtration chromatography followed by reversed-phase HPLC. The purified protein was fully characterized by electrophoresis, amino acid analysis, atomic absorption spectroscopy and elemental analysis, and was shown to contain 10 +/- 2 Cu(I) per molecule of protein. Small angle X-ray scattering measurements yielded a radius of gyration of 1.2 nm for the recombinant protein, indicating a more extended structure in solution than that derived from the recent NMR data [Peterson, C.W., Narula, S.S. & Armitage, I.A. (1996) FEBS Lett. 379, 85-93].


Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naïve patients with early rheumatoid arthritis.
Subjects with rheumatoid arthritis (RA) have increased cardiovascular risk and may show atherogenic forms of dyslipidemia. The present study investigated whether patients with early RA, beyond alterations in plasma lipids, also show lower LDL size and altered LDL subclass distribution. We identified 25 subjects with RA (47+/-8 years, body mass index (BMI) 25+/-4kg/m(2)) by the American College of Rheumatology diagnostic criteria, with a disease durations <1 year and no prior treatment against it. In patients and 22 healthy subjects matched for age and BMI (controls) we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis. As compared to controls RA patients had higher plasma triglycerides (1.8+/-0.5 vs. 1.0+/-0.5mmol/L, p<0.0001) and lower HDL-cholesterol concentrations (1.2+/-0.2 vs. 1.4+/-0.2mmol/L, p=0.0027), while total- and LDL-cholesterol concentrations were similar. LDL particle size was lower in RA patients than controls (264+/-7 vs. 281+/-9A, p<0.0001), due to less LDL-I (31+/-6 vs. 38+/-7%, p=0.0004) and LDL-IIA (14+/-3 vs. 16+/-3%, p=0.0182), and more LDL-IIIB (7+/-1 vs. 5+/-1%), -IVA (11+/-2 vs. 8+/-2%) and -IVB particles (12+/-2 vs. 9+/-2%,) (p<0.0001 for all). Further, about 1/3 of patients showed the complete "atherogenic-lipoprotein-phenotype" (e.g. the concomitant presence of high triglycerides, low HDL-cholesterol and elevated small, dense LDL). Beyond plasma lipids, increased levels of small, dense LDL seems to be common in drug-naïve patients with early RA. Yet, whether these findings affect the atherogenic process and the clinical endpoints in these subjects remains to be determined by future prospective studies.


Effectiveness of nurse-led brief alcohol intervention: a cluster randomized controlled trial.
This paper reports an evaluation of the effectiveness and cost-effectiveness of nurse-led screening and brief intervention in reducing excessive alcohol consumption among patients in primary health care. Excessive alcohol consumption is a major source of social, economic and health problems. However, such consumption is responsive to brief alcohol intervention. To date, brief intervention research in primary health care has focused on general practitioner-led interventions, and there is only circumstantial evidence of effectiveness in nurse-led interventions. However, nurses are increasingly taking a lead in health promotion work in primary care. A pragmatic cluster-randomized controlled trial was carried out between August 2000 and June 2003 to evaluate the effects of a brief intervention compared with standard advice (control condition). A total of 40 general practice clusters (intervention = 21 and control = 19) recruited 127 patients (intervention = 67 and control = 60) to the trial. Excessive consumption was identified opportunistically via the Alcohol Use Disorders Identification Test. After baseline assessment, patients received either a 5-10 minutes brief intervention using the 'Drink-Less' protocol or standard advice (control condition). Follow-up occurred at 6 and 12 months postintervention. Analysis of variance weighted for cluster size revealed no statistically significant differences between intervention and control patients at follow up. A majority of patients in both conditions reduced their alcohol consumption between assessment and subsequent measurement. Economic analysis suggested that the brief intervention led to no statistically significant changes in subsequent health service resource use relative to standard treatment. The brief intervention evaluated in this trial had no effect over standard advice delivered by nurses in primary health care. However, there was a reduction in excessive drinking across both arms of the trial over time. Due to nurse drop-out, this trial was significantly underpowered. Future research should explore barriers to nurses' involvement in research trials, particularly with an alcohol focus. A larger trial is required to evaluate the effectiveness of nurse-led screening and brief alcohol intervention in primary care.


Adherence to antithrombotic therapy guidelines improves mortality among elderly patients with atrial fibrillation: insights from the REPOSI study.
Atrial fibrillation (AF) is associated with a substantial risk of thromboembolism and mortality, significantly reduced by oral anticoagulation. Adherence to guidelines may lower the risks for both all cause and cardiovascular (CV) deaths. Our objective was to evaluate if antithrombotic prophylaxis according to the 2012 European Society of Cardiology (ESC) guidelines is associated to a lower rate of adverse outcomes. Data were obtained from REPOSI; a prospective observational study enrolling inpatients aged ≥65 years. Patients enrolled in 2012 and 2014 discharged with an AF diagnosis were analysed. Among 2535 patients, 558 (22.0 %) were discharged with a diagnosis of AF. Based on ESC guidelines, 40.9 % of patients were on guideline-adherent thromboprophylaxis, 6.8 % were overtreated, and 52.3 % were undertreated. Logistic analysis showed that increasing age (p = 0.01), heart failure (p = 0.04), coronary artery disease (p = 0.013), peripheral arterial disease (p = 0.03) and concomitant cancer (p = 0.003) were associated with non-adherence to guidelines. Specifically, undertreatment was significantly associated with increasing age (p = 0.001) and cancer (p < 0.001), and inversely associated with HF (p = 0.023). AF patients who were guideline adherent had a lower rate of both all-cause death (p = 0.007) and CV death (p = 0.024) compared to those non-adherent. Kaplan-Meier analysis showed that guideline-adherent patients had a lower cumulative risk for both all-cause (p = 0.002) and CV deaths (p = 0.011). On Cox regression analysis, guideline adherence was independently associated with a lower risk of all-cause and CV deaths (p = 0.019 and p = 0.006). Non-adherence to guidelines is highly prevalent among elderly AF patients, despite guideline-adherent treatment being independently associated with lower risk of all-cause and CV deaths. Efforts to improve guideline adherence would lead to better outcomes for elderly AF patients.


A determination of emergency department pre-triage times in patients not arriving by ambulance compared to widely used guideline recommendations.
Emergency department (ED) lengths of stay are measured from the time of patient registration or triage. The time that patients wait in line prior to registration and triage has not been well described. We sought to characterize pre-triage wait times and compare them to recommended physician response times, as per the Canadian Triage and Acuity Scale (CTAS). This observational study documented the time that consenting patients entered the ED and the time that they were formally registered and triaged. Participants' CTAS scores were collected from the electronic record. Patients arriving to the ED by ambulance were excluded. A total of 536 participants were timed over 13 separate intervals. Of these, 11 left without being triaged. Participants who scored either CTAS 1 or 2 (n=53) waited a median time of 3.1 (interquartile range [IQR]: 0.43, 11.1) minutes. Patients triaged as CTAS 3 (n=187) waited a median of 11.4 (IQR: 1.6, 24.9) minutes, CTAS 4 (n=139) a median of 16.6 (IQR: 6.0, 29.7) minutes, and CTAS 5 (n=146) a median of 17.5 (IQR: 6.8, 37.3) minutes. Of patients subsequently categorized as CTAS 1 or 2, 20.8% waited longer than the recommended time-to-physician of 15 minutes to be triaged. All urban EDs closely follow patients' wait times, often stratified according to triage category, which are assumed to be time-stamped upon a patient's arrival in the ED. We note that pre-triage times exceed the CTAS recommended time-to-physician in a possibly significant proportion of patients. EDs should consider documenting times to treatment from the moment of patient arrival rather than registration.


Graphene and hydroxyapatite self-assemble into homogeneous, free standing nanocomposite hydrogels for bone tissue engineering.
Graphene-nanoparticle (NP) composites have shown potential in applications ranging from batteries to, more recently, tissue engineering. Graphene and NPs should be integrated into uniform free-standing structures for best results. However, to date, this has been achieved only in few examples; in most cases, graphene/NP powders lacking three-dimensional (3D) structure were produced. Here we report a facile and universal method that can be used to synthesize such structures based on colloidal chemistry. We start from aqueous suspensions of both graphene oxide nanosheets and citrate-stabilized hydroxyapatite (HA) NPs. Hydrothermal treatment of the mixtures of both suspensions reduces graphene oxide to graphene, and entraps colloidal HA NPs into the 3D graphene network thanks to a self-assembled graphite-like shell formed around it. Dialysis through this shell causes uniform NP deposition onto the graphene walls. The resulting graphene-HA gels are highly porous, strong, electrically conductive and biocompatible, making them promising scaffolds for bone tissue engineering. This method can be applied to produce a variety of free-standing 3D graphene-based nanocomposites with unprecedented homogeneity.


Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.
Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role. Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin. Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis). HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.


Lactate threshold and performance adaptations to 4 weeks of training in untrained swimmers: volume vs. intensity.
The purpose of this study was to investigate the impact of 4 weeks of high-intensity vs. high-volume swim training on lactate threshold (LT) characteristics and performance. Thirteen untrained swimmers with a mean age of 19.0 ± 0.5 undertook an incremental swimming test before and after 4 weeks of training for the determination of LT. Performance was evaluated by a 50-m maximum freestyle test. The swimmers were assigned to 1 of each of 2 training groups. The high-intensity group (n = 6) focused on sprint training (SP) and swam a total of 1,808 ± 210 m. The high-volume group (n = 7) followed the same program as the SP group but swam an additional 1,100 m (38% more) of endurance swimming (SP + End). A training effect was evident in both groups as seen by the similar improvements in sprint performance of the 50-m maximum time (p < 0.01), peak velocity increases and the lower value of lactate at the individual LTs (p < 0.01). Lactate threshold velocity improved only in the SP + End group from 1.20 ± 0.12 m·s(-1) pretraining to 1.32 ± 0.12 m·s(-1) posttraining (p = 0.77, effect size = 1, p < 0.01), expressed by the rightward shifts of the individual lactate-velocity curves, indicating an improvement in the aerobic capacity. Peak lactate and lactate concentrations at LT did not significantly change. In conclusion, this study was able to demonstrate that 4 weeks of either high-intensity or high-volume training was able to demonstrate similar improvements in swimming performance. In the case of lack of significant changes in lactate profiling in response to high-intensity training, we could suggest a dissociation between the 2.


Entanglement Entropy of the ν=1/2 Composite Fermion Non-Fermi Liquid State.
The so-called "non-Fermi liquid" behavior is very common in strongly correlated systems. However, its operational definition in terms of "what it is not" is a major obstacle for the theoretical understanding of this fascinating correlated state. Recently there has been much interest in entanglement entropy as a theoretical tool to study non-Fermi liquids. So far explicit calculations have been limited to models without direct experimental realizations. Here we focus on a two-dimensional electron fluid under magnetic field and filling fraction ν=1/2, which is believed to be a non-Fermi liquid state. Using a composite fermion wave function which captures the ν=1/2 state very accurately, we compute the second Rényi entropy using the variational Monte Carlo technique. We find the entanglement entropy scales as LlogL with the length of the boundary L as it does for free fermions, but has a prefactor twice that of free fermions.


Neighborhood property-based pattern selection for support vector machines.
The support vector machine (SVM) has been spotlighted in the machine learning community because of its theoretical soundness and practical performance. When applied to a large data set, however, it requires a large memory and a long time for training. To cope with the practical difficulty, we propose a pattern selection algorithm based on neighborhood properties. The idea is to select only the patterns that are likely to be located near the decision boundary. Those patterns are expected to be more informative than the randomly selected patterns. The experimental results provide promising evidence that it is possible to successfully employ the proposed algorithm ahead of SVM training.


Distribution of fitness effects caused by random insertion mutations in Escherichia coli.
Very little is known about the distribution of mutational effects on organismal fitness, despite the fundamental importance of this information for the study of evolution. This lack of information reflects the fact that it is generally difficult to quantify the dynamic effects of mutation and natural selection using only static distributions of allele frequencies. In this study, we took a direct approach to measuring the effects of mutations on fitness. We used transposon-mutagenesis to create 226 mutant clones of Escherichia coli. Each mutant clone carried a single random insertion of a derivative of Tn10. All 226 mutants were independently derived from the same progenitor clone, which was obtained from a population that had evolved in a constant laboratory environment for 10,000 generations. We then performed competition experiments to measure the effect of each mutation on fitness relative to a common competitor. At least 80% of the mutations had a significant negative effect on fitness, whereas none of the mutations had a significant positive effect. The mutations reduced fitness by about 3%, on average, but the distribution of fitness effects was highly skewed and had a long, flat tail. A compound distribution, which includes both gamma and uniform components, provided an excellent fit to the observed fitness values.


Autophagy induced by calcium phosphate precipitates targets damaged endosomes.
Calcium phosphate precipitates (CPPs) form complexes with DNA, which enter cells via endocytosis. Under this condition CPPs induce autophagy via the canonic autophagy machinery. Here we showed that CPP-induced autophagy was also dependent on endocytosis as the process was significantly inhibited by methyl-β-cyclodextrin and dynasore, which suppress clathrin-dependent endocytosis. Consistently, CPP treatment triggered the formation of filipin-positive intracellular vesicles whose membranes are rich in cholesterol. Unexpectedly, these vesicles were also positive for galectin 3, suggesting that they were damaged and the membrane glycans became accessible to galectins to bind. Endosome damage was caused by endocytosis of CPPs and was reversed by calcium chelators or by endocytosis inhibitors. Notably, CPP-induced LC3-positive autophagosomes were colocalized with galectin 3, ubiquitin, and p62/SQSTM1. Inhibition of galectin 3 reduced p62 puncta and autophagosome formation. Knockdown of p62 additionally inhibited the colocalization of autophagosomes with galectins. Furthermore, most of the galectin 3-positive vesicles were colocalized with Rab7 or LAMP1. Agents that affect endosome/lysosome maturation and function, such as bafilomycin A1, also significantly affected CPP-induced tubulovesicular autophagosome formation. These findings thus indicate that endocytosed CPPs caused endosome damage and recruitment of galectins, particularly at the later endosome stage, which led to the interaction of the autophagosomal membranes with the damaged endosome in the presence of p62.


A comparative method for finding and folding RNA secondary structures within protein-coding regions.
Existing computational methods for RNA secondary-structure prediction tacitly assume RNA to only encode functional RNA structures. However, experimental studies have revealed that some RNA sequences, e.g. compact viral genomes, can simultaneously encode functional RNA structures as well as proteins, and evidence is accumulating that this phenomenon may also be found in Eukaryotes. We here present the first comparative method, called RNA-DECODER, which explicitly takes the known protein-coding context of an RNA-sequence alignment into account in order to predict evolutionarily conserved secondary-structure elements, which may span both coding and non-coding regions. RNA-DECODER employs a stochastic context-free grammar together with a set of carefully devised phylogenetic substitution-models, which can disentangle and evaluate the different kinds of overlapping evolutionary constraints which arise. We show that RNA-DECODER's parameters can be automatically trained to successfully fold known secondary structures within the HCV genome. We scan the genomes of HCV and polio virus for conserved secondary-structure elements, and analyze performance as a function of available evolutionary information. On known secondary structures, RNA-DECODER shows a sensitivity similar to the programs MFOLD, PFOLD and RNAALIFOLD. When scanning the entire genomes of HCV and polio virus for structure elements, RNA-DECODER's results indicate a markedly higher specificity than MFOLD, PFOLD and RNAALIFOLD.


Explantation of High Submuscular Reservoirs: Safety and Practical Considerations.
Over the past decade, high submuscular (HSM) placement of inflatable penile prosthesis (IPP) reservoirs has emerged as a viable alternative to space of Retzius (SOR) placement; however, data comparing the feasibility and complications of HSM vs SOR reservoir removal do not presently exist. To present a comparison of the safety, feasibility, and ease of removal of HSM vs SOR reservoirs in a tertiary care, university-based, high-volume prosthetic urology practice. Data were retrospectively collected on patients who underwent IPP reservoir removal between January 2011 and June 2020. Cases were separated into 2 cohorts based on reservoir location. Statistical analysis was performed using Fisher's exact and Chi-squared tests for categorical variables and Student's t-test for continuous variables. Timing from IPP insertion to explant was compared between the HSM and SOR groups using the Mann-Whitney U test. Time from IPP insertion to explant, operative time, intraoperative and postoperative complications, and need for a counter incision were compared between the HSM and SOR groups. Between January 2011 and June 2020, 106 (73 HSM, 33 SOR) patients underwent IPP removal or replacement by a single surgeon at our institution. Average time from IPP insertion to removal was 43.6 months (24.2 HSM, 52.7 SOR, P = .07)-reservoir removal occurred at the time of device explant in 70 of 106 (66%) cases. More HSM reservoirs were explanted at the time of IPP removal compared with the SOR cohort (54 of 73, 74% HSM vs 16 of 33, 48.5% SOR, P = .01). Similar rates of complications were noted between the HSM and SOR groups (1.9% vs 6.3%, P = .35). There was no significant difference in need for counter incision between the 2 groups (24 [42%] HSM vs 4 [25%] SOR, P = .16) or in average operative times (76.5 ± 38.3 minutes HSM vs 68.1 ± 34.3 minutes SOR, P = .52). Our experience with explanting HSM reservoirs supports the safety and ease of their removal. Although the absolute cohort size is relatively low, this study reflects one of the largest single-institution experiences examining penile implant reservoir removal. In addition, reservoir location was not randomized but was instead determined by which patients presented with complications necessitating reservoir removal during the study period. HSM reservoir removal has comparable perioperative complication rates and operative times when compared with SOR reservoir removal. Kavoussi M, Bhanvadia RR, VanDyke ME, et al. Explantation of High Submuscular Reservoirs: Safety and Practical Considerations. J Sex Med 2020;17:2488-2494.