Using Design Thinking to Improve Psychological Interventions: The Case of the Growth Mindset During the Transition to High School.
There are many promising psychological interventions on the horizon, but there is no clear methodology for preparing them to be scaled up. Drawing on design thinking, the present research formalizes a methodology for redesigning and tailoring initial interventions. We test the methodology using the case of fixed versus growth mindsets during the transition to high school. Qualitative inquiry and rapid, iterative, randomized "A/B" experiments were conducted with ~3,000 participants to inform intervention revisions for this population. Next, two experimental evaluations showed that the revised growth mindset intervention was an improvement over previous versions in terms of short-term proxy outcomes (Study 1, N=7,501), and it improved 9th grade core-course GPA and reduced D/F GPAs for lower achieving students when delivered via the Internet under routine conditions with ~95% of students at 10 schools (Study 2, N=3,676). Although the intervention could still be improved even further, the current research provides a model for how to improve and scale interventions that begin to address pressing educational problems. It also provides insight into how to teach a growth mindset more effectively.


Does social defeat mediate the association between childhood trauma and psychosis? Evidence from the NEMESIS-2 Study.
Based on theoretical considerations and animal studies, mediation of 'social defeat' (SD) in the association between childhood trauma (CT) and psychosis was investigated. Trained interviewers administered a structured interview assessing CT, psychotic experiences and other psychopathology in 6646 participants in the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Childhood trauma was associated with psychotic experiences making up the extended psychosis phenotype (EPP), as well as with a diagnosis of psychotic disorder (PD). Similarly, CT was associated with a priori selected items indexing SD (discouraged, hopeless, worthless, loss of self-confidence, low self-esteem, better off dead, suicidal thoughts) and with a measure of affective dysregulation (AD), which in turn were also associated with psychosis. While SD and AD individually acted as mediators in the association between CT and EPP, only SD acted as a mediator in the association between CT and PD. Cannabis use did not mediate the association between CT and EPP or PD. The present results suggest a developmental model implicating SD as an important mediator in the link between childhood adverse experiences and later development of psychotic experiences. The combined mediation by SD and AD is compatible with an 'affective pathway' to early psychosis.


Modeling the performance of image restoration from motion blur.
When dealing with motion blur there is an inevitable trade-off between the amount of blur and the amount of noise in the acquired images. The effectiveness of any restoration algorithm typically depends on these amounts, and it is difficult to find their best balance in order to ease the restoration task. To face this problem, we provide a methodology for deriving a statistical model of the restoration performance of a given deblurring algorithm in case of arbitrary motion. Each restoration-error model allows us to investigate how the restoration performance of the corresponding algorithm varies as the blur due to motion develops. Our modeling treats the point-spread-function trajectories as random processes and, following a Monte-Carlo approach, expresses the restoration performance as the expectation of the restoration error conditioned on some motion-randomness descriptors and on the exposure time. This allows to coherently encompass various imaging scenarios, including camera shake and uniform (rectilinear) motion, and, for each of these, identify the specific exposure time that maximizes the image quality after deblurring.


DNA fingerprinting of Streptococcus pneumoniae strains by pulsed-field gel electrophoresis.
Pulsed-field gel electrophoresis of genomic DNA was carried out on Streptococcus pneumoniae strains to determine its value in the epidemiological survey of pneumococcal infections. Twenty-one clinical strains were chosen to cover a broad range of diversity according to geographic location, penicillin susceptibility, serotype, and multilocus enzyme electrophoresis (MLEE) pattern. The restriction endonucleases ApaI and SmaI were used to digest intact chromosomes, and the fragments were resolved by field inversion gel electrophoresis (FIGE). Each digest produced 10 to 19 fragments for comparison between strains. All the strains, including strains of the same serotype and strains with the same MLEE profile, had different FIGE patterns. In some cases, the restriction patterns differed by only a few fragment bands, and two isolates differed only in the location of a single DNA fragment. The polymorphism obtained with FIGE was greater than those obtained with serotyping and MLEE analysis. The stability of the FIGE profiles was established by testing of two independent clones derived from pneumococcus strain R36A. These results indicated that pulsed-field gel electrophoresis should be an effective tool for the typing of S. pneumoniae strains, capable of subdividing serotypes or MLEE types and of tracing the origin of pneumococcal strains.


Psychometric analysis of the Life Worries Scale for a new generation of sexual minority men: The P18 Cohort Study.
Sexual minority men (SMM) in the United States continue to experience adverse health problems and psychosocial burdens. However, there is limited psychometric research seeking to quantify the life worries of this population. Informed by syndemic theory, the Life Worries Scale (LWS) was developed to measure the concerns of young SMM. Analyses of the scale were undertaken using baseline data (n = 665) from an ongoing cohort study of emerging adult, SMM. Exploratory factor analyses (EFA) of an initial set of 24 Likert-type items, followed by confirmatory factor analysis (CFA) and an exploratory structural equation model (ESEM), indicated a structure consisting of 6 domains of worries: financial stability, social stability, self esteem, loneliness, physical appearance, and physical health. These 6 subscales were highly correlated and also demonstrated high levels of internal consistency. Differences in life worries were noted across demographic states, specifically HIV serostatus, sexual attraction, housing status, and self-rated health. High levels of association were also detected between all 6 subscales with both depression and PTSD, while significant correlations were detected between suicidality and both self esteem and loneliness related worries. The results of our analyses provide evidence for the strong psychometric characteristics of the LWS. This newly developed instrument should be utilized in research to examine the extent to which life worries explain health outcomes and risk behaviors in sexual minority males, and may be potentially extended for use in other populations. (PsycINFO Database Record


Total cavopulmonary connection in patients with apicocaval juxtaposition: optimal conduit route using preoperative angiogram and flow simulation.
Single ventricle with apicocaval juxtaposition (ACJ) is a rare, complex anomaly, in which the optimal position of the conduit for completion of total cavopulmonary connection (TCPC) is still controversial. The purpose of this study was to identify a preoperative method for optimal conduit position using the IVC anatomy and computational fluid dynamics (CFD). Twenty-four patients with ACJ (5.3 ± 5.7 years) who underwent TCPC were enrolled. A conduit was placed ipsilateral to the cardiac apex in each of 11 patients, of which 9 were intra-atrial and 2 extracardiac (group A) and, in a further 13 patients, extracardiac on the contralateral side (group B). As control, 10 patients with tricuspid atresia were also enrolled (group C). The location of the IVC in relation to the spine was evaluated from the frontal view of preoperative angiogram, using the following index: IVC-index = IVC width overlapping the vertebra/width of the vertebra × 100%. Energy loss was calculated by CFD simulation. IVC-index of group B was larger than groups A and C (45 ± 26 vs. 20 ± 21 and 28 ± 19%, P = 0.03). Postoperative catheterizations showed that, due to its curvature, conduit length in group B was significantly longer than the others (65 ± 12 vs. 36 ± 14 and 44 ± 10 mm, P < 0.001), although there was no statistical difference in central venous pressure or cardiac output. CFD studies revealed less energy loss in group A conduits compared with group B (1.6 ± 0.3 vs. 3.6 ± 0.6 mW, P = 0.05), although this did not appear to be clinically significant. Moreover, CFD simulation showed significant energy loss within the Fontan circulation when the conduit was either compressed or kinked: 4.9 and 18.2 mW respectively. In patients with ACJ, placement of a straighter and shorter conduit on the ventricular apical side provides better laminar blood flow with less energy loss. However, conduit compression and kinking are far more detrimental to the Fontan circulation. A preoperative IVC-index is pivotal for avoiding these factors and deciding the optimal conduit route.


Multiple inhalers confuse asthma patients.
This study investigated the influence of the use of different types of inhalers on the adequacy of inhalation technique among adult asthmatics. Three hypotheses were tested: first, patients using only one type of inhaler will demonstrate adequate inhalation technique more often than those with two or more types. Secondly, patients using a combination of dry powder inhalers (DPIs) will demonstrate correct inhalation technique more often than those using the combination of a metered dose inhaler (MDI) and a DPI. Thirdly, some inhalers or combinations of inhalers are more prone to erroneous inhalation technique than others. Adult outpatients with asthma who regularly used inhaled steroid therapy (n=321) participated in the study. The inhalers investigated were MDIs on the one hand, and the DPIs Turbuhaler, Diskhaler, Cyclohaler, Inhaler Ingelheim and Rotahaler on the other. Of 208 adult asthmatics with only one inhaler, 71% made no inhalation errors versus 61% of 113 patients with two or more different inhalers. Of patients with a combination of DPIs 68% performed all essential checklist items correctly, versus 54% of patients with the combination of "regular" MDI and DPI. Patients using only the Diskhaler made fewest errors. Whenever possible, only one type of inhaler should be prescribed. If a combination is unavoidable, combinations of DPIs are preferable to MDI and DPI. The Diskhaler seems to be the most foolproof device.


Prospective Associations between Sport Participation and Indices of Mental Health across Adolescence.
Youth sport offers physical and psychosocial components that may be beneficial for adolescents' mental health, but the prospective directionality between sport participation and mental health has not been clearly established. The current study examined longitudinal associations between sport participation (individual and team sport) and mental health indices (depressive symptoms, anxiety symptoms, emotional symptoms, hyperactivity symptoms, conduct problems, peer problems, and prosocial behavior) across adolescence (ages 12-17) in a nationally representative Australian sample of 3956 participants at T1 (Mage = 12.41 years, SD = 0.49; 49% female), 3537 at T2 (Mage = 14.41 years, SD = 0.49; 49% female), and 3089 at T3 (Mage = 16.46 years, SD = 0.51; 49% female). Using random intercept cross-lagged panel modeling, several significant within-person effects were found. Notably, greater participation in team sport prospectively predicted fewer symptoms of depression and anxiety at subsequent timepoints. This study increases the understanding of how sport participation may relate to mental health among adolescents and provides critical evidence to inform policy.


Electron-triggered chemistry in HNO3/H2O complexes.
Polar stratospheric clouds, which consist mainly of nitric acid containing ice particles, play a pivotal role in stratospheric chemistry. We investigate mixed nitric acid-water clusters (HNO3)m(H2O)n, m ≈ 1-6, n ≈ 1-15, in a laboratory molecular beam experiment using electron attachment and mass spectrometry and interpret our experiments using DFT calculations. The reactions are triggered by the attachment of free electrons (0-14 eV) which leads to subsequent intracluster ion-molecule reactions. In these reactions, the nitrate anion NO3- turns out to play the central role. This contradicts the electron attachment to the gas-phase HNO3 molecule, which leads almost exclusively to NO2-. The nitrate containing clusters are formed through at least three different reaction pathways and represent terminal product ions in the reaction cascade initiated by the electron attachment. Besides, the complex reaction pathways represent a new hitherto unrecognized source of atmospherically important OH and HONO molecules.


Clinical and immunological studies of cadaveric renal transplant recipients given total-lymphoid irradiation and maintained on low-dose prednisone.
Twenty-five recipients of cadaveric renal transplants were given total lymphoid irradiation (TLI), perioperative antithymocyte globulin, and low-dose prednisone as the sole maintenance immunosuppressive drug. Nine patients were diabetic, and follow-up was between 19 and 37 months. One-year graft and patient survival was 76% and 87%, respectively, Serious complications included four deaths from cardiovascular disorders, and two deaths from viral infections. Studies of peripheral blood T cell subsets showed a prolonged reduction in the absolute number of helper (Leu-3+) cells, and a rapid recovery of cytotoxic/suppressor (Leu-2+) cells. Analysis of the latter subset, using the monoclonal antibody 9.3, showed that the ratio of suppressor/cytotoxic cells was approximately 10:1. The normal ratio is 1:1. The mean mixed leukocyte reaction remained below 30% of the pre-TLI value for 6 months, and approached 80% at two years. Similar kinetics were observed in the proliferative response to mitogens. The results show that maintenance immunosuppressive drug therapy can be reduced after TLI as compared with conventional drug regimens that use prednisone in combination with cyclosporine and/or azathioprine.


Clinical Characteristics of Imported Cases of Coronavirus Disease 2019 (COVID-19) in Jiangsu Province: A Multicenter Descriptive Study.
We aimed to report the clinical characteristics of imported cases of coronavirus disease 2019 (COVID-19) in Jiangsu Province. We retrospectively investigated the clinical, imaging, and laboratory characteristics of confirmed cases of COVID-19 with World Health Organization interim guidance in 3 grade IIIA hospitals of Jiangsu from 22 January to 14 February 2020. Real-time RT-PCR was used to detect the new coronavirus in respiratory samples. Of the 80 patients infected with COVID-19, 41 were female, with a median age of 46.1 years. Except for 3 severe patients, the rest of the 77 patients exhibited mild or moderate symptoms. Nine patients were unconfirmed until a third nucleic acid test; 38 cases had a history of chronic diseases. The main clinical manifestations of the patients were fever and cough, which accounted for 63 (78.75%) and 51 (63.75%) cases, respectively. Only 3 patients (3.75%) showed liver dysfunction. Imaging examination showed that 55 patients (68.75%) showed abnormal density shadow and 25 cases (31.25%) had no abnormal density shadow in the parenchyma of both lungs. Currently, 21 cases have been discharged from the hospital, and no patient died. The average length of stay for discharged patients was 8 days. Compared with the cases in Wuhan, the cases in Jiangsu exhibited mild or moderate symptoms and no obvious gender susceptibility. The proportion of patients having liver dysfunction and abnormal CT imaging was relatively lower than that in Wuhan. Notably, infected patients may be falsely excluded based on 2 consecutively negative respiratory pathogenic nucleic acid test results.


Crystallographic and mass spectrometric characterisation of eIF4E with N7-alkylated cap derivatives.
Structural complexes of the eukaryotic translation initiation factor 4E (eIF4E) with a series of N(7)-alkylated guanosine derivative mRNA cap analogue structures have been characterised. Mass spectrometry was used to determine apparent gas-phase equilibrium dissociation constants (K(d)) values of 0.15 microM, 13.6 microM, and 55.7 microM for eIF4E with 7-methyl-GTP (m(7)GTP), GTP, and GMP, respectively. For tight and specific binding to the eIF4E mononucleotide binding site, there seems to be a clear requirement for guanosine derivatives to possess both the delocalised positive charge of the N(7)-methylated guanine system and at least one phosphate group. We show that the N(7)-benzylated monophosphates 7-benzyl-GMP (Bn(7)GMP) and 7-(p-fluorobenzyl)-GMP (FBn(7)GMP) bind eIF4E substantially more tightly than non-N(7)-alkylated guanosine derivatives (K(d) values of 7.0 microM and 2.0 microM, respectively). The eIF4E complex crystal structures with Bn(7)GMP and FBn(7)GMP show that additional favourable contacts of the benzyl groups with eIF4E contribute binding energy that compensates for loss of the beta and gamma-phosphates. The N(7)-benzyl groups pack into a hydrophobic pocket behind the two tryptophan side-chains that are involved in the cation-pi stacking interaction between the cap and the eIF4E mononucleotide binding site. This pocket is formed by an induced fit in which one of the tryptophan residues involved in cap binding flips through 180 degrees relative to structures with N(7)-methylated cap derivatives. This and other observations made here will be useful in the design of new families of eIF4E inhibitors, which may have potential therapeutic applications in cancer.


Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes in a bioartificial liver.
This study was designed to determine if an anti-necrotic compound, glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and function of hepatocytes in a bioartificial liver. Isolated rat hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined after anoxic exposure (0-20 hours). Cell functionality (measured by urea production), cell viability (quantitated by vital staining with fluorescein diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified by electron microscopy and DNA fragmentation studies) were determined for each condition. The viability of GERH declined gradually and then stabilized 12 hours after hepatocyte isolation. The rate of urea production by GERH was directly proportional to the number of viable hepatocytes. Apoptotic death predominated at low cell density, and necrotic cell death became significant at high cell density. Hepatocyte necrosis became more significant after exposure to longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose-dependent cytoprotection to GERH with an optimum benefit at a concentration of 60 mumol/L. After anoxic exposure or under high cell density culture, glycine demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3 mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive. The metabolic activity of a hepatocyte bioartificial liver may benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.


Women in rural family medicine: a qualitative exploration of practice attributes that promote physician satisfaction.
The USA needs more rural physicians. Although women represent half of all US trained medical students, the rural physician workforce has remained predominantly male. Insight is needed into what makes rural practice attractive for women and which practice characteristics allow women physicians to practice successfully in rural areas. This study's purpose was to examine aspects of the practice environment that impact women physicians' professional satisfaction and commitment to rural medicine. Twenty-five women family physicians practicing in rural areas of the USA were interviewed by phone using a semi-structured format. Transcribed interviews were analyzed using an immersion and crystallization approach. Emergent themes were identified, coded, and discussed until team consensus was attained. Interviews continued until saturation of themes was reached. Three themes emerged from the data, in relationship to practice and employment attributes that contribute to US women physicians' professional satisfaction and willingness to remain in a rural setting: professional relationships, practice characteristics, and support during times of transition. Participants placed high importance on professional relationships, both within and outside of their rural practice. Rural women physicians enjoyed practicing an expanded scope of care, valued loan repayment opportunities, and appreciated supportive practice partners. Importantly, women physicians who found themselves struggling to maintain rural careers often had experienced difficulty during times of practice transition, including maternity leaves. Understanding practice attributes valued by successful rural women family physicians in the USA will help rural health systems, practices, and physicians-in-training to develop and evaluate opportunities that will best contribute to successful rural practice. Supporting women physicians during periods of practice transition may improve retention.


The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.
Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.


Reactivity of integrin-linked kinase in human mesothelial cell proliferation.
Integrin-linked kinase (ILK) is a protein kinase that links integrins and growth factors to a range of signalling pathways. ILK expression and activity are increased in a variety of human cancers. However, little is known regarding the role of ILK in malignant pleural mesothelioma (MPM). In this study, we assessed the expression of ILK in samples of human MPM, and compared it with the expression of epidermal growth factor receptor (EGFR). Thirty-four samples of human malignant mesothelioma were stained with a polyclonal antibody against ILK. Two independent observers evaluated the morphological pattern and intensity of staining. The findings have been compared with the patient's characteristics. Most MPM and mesothelial cell proliferation samples (87.9%) showed cytoplasmic ILK staining of varying intensity. Normal mesothelial cells and normal lung parenchyma did not stain for ILK at all. Conversely, the percentage of positive EGFR staining was somewhat lower (75.8%). The ILK-positive patients were significantly older than the ILK-negative patients. Here we report for the first time that ILK is indeed expressed in malignant mesothelioma. For further validation of a causal association between ILK and neoplastic mesothelial transformation, these immunohistochemical results should be supplemented with clinical and molecular biological data.


A comparison between neural response telemetry via cochleostomy or the round window approach in cochlear implantation.
There are two techniques for cochlear implant (CI) electrode placement: cochleostomy and the round window (RW) approach. This study aims to compare neural response telemetry (NRT) results immediately after surgery to check for possible differences on auditory nerve stimulation between these two techniques. This is a prospective cross-sectional study. Twenty-three patients were enrolled. Six patients underwent surgery by cochleostomy and 17 had it through the RW approach. Mean charge units (MCU) for high frequency sounds: patients submitted to the RW approach had a mean value of 190.4 (± 29.2) while cochleostomy patients averaged 187.8 (± 32.7); p = 0.71. MCU for mid frequency sounds: patients submitted to the RW approach had a mean value of 192.5 (± 22) while cochleostomy patients averaged 178.5 (± 18.5); p = 0.23. MCU for low frequency sounds: patients submitted to the RW approach had a mean value of 183.3 (± 25) while cochleostomy patients averaged 163.8 (± 19.3); p = 0.19. This study showed no differences in the action potential of the distal portion of the auditory nerve in patients with multichannel cochlear implants submitted to surgery by cochleostomy or through the RW approach, using the implant itself to generate stimuli and record responses. Both techniques equally stimulate the cochlear nerve. Therefore, the choice of approach can be made based on the surgeon's own preference and experience.


Regulated expression of the neural cell adhesion molecule L1 by specific patterns of neural impulses.
Development of the mammalian nervous system is regulated by neural impulse activity, but the molecular mechanisms are not well understood. If cell recognition molecules [for example, L1 and the neural cell adhesion molecule (NCAM)] were influenced by specific patterns of impulse activity, cell-cell interactions controlling nervous system structure could be regulated by nervous system function at critical stages of development. Low-frequency electrical pulses delivered to mouse sensory neurons in culture (0.1 hertz for 5 days) down-regulated expression of L1 messenger RNA and protein (but not NCAM). Fasciculation of neurites, adhesion of neuroblastoma cells, and the number of Schwann cells on neurites was reduced after 0.1-hertz stimulation, but higher frequencies or stimulation after synaptogenesis were without effect.


Local production of medical technologies and its effect on access in low and middle income countries: a systematic review of the literature.
The objective of this study was to assess the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products. Our preliminary hypothesis is that studies showing a robust relationship between local production and access to medical products are sparse, at best. An extensive literature search was conducted using a wide variety of databases and search terms intending to capture as many different aspects of this issue as possible. The results of the search were reviewed and categorized according to their relevance to the research question. The literature was also reviewed to determine the rigor used to examine the effects of local production and what implications these experiences hold for other developing countries. Literature addressing the benefits of local production and the link between it and access to medical products is sparse, mainly descriptive and lacking empirical evidence. Of the literature we reviewed that addressed comparative economics and strategic planning of multinational and domestic firms, there are few dealing with emerging markets and lower-middle income countries and even fewer that compare local biomedical producers with multinational corporations in terms of a reasonable metric. What comparisons exist mainly relate to prices of local versus foreign/multinational produced medicines. An assessment of the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products reveals a paucity of literature explicitly dealing with this issue. Of the literature that does exist, methods used to date are insufficient to prove a robust relationship between local production of medical products and access to these products. There are mixed messages from various studies, and although the studies may correctly depict specific situations in specific countries with reference to specific products, such evidence cannot be generalized. Our review strongly supports the need for further research in understanding the dynamic link between local production and access to medical products.


Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia.
Chemotherapy leads to an increase in reactive oxygen species, which stresses the antioxidant defense system. Children with acute lymphoblastic leukemia rarely are overtly malnourished, which makes this population ideal for an investigation of the relations between dietary antioxidant consumption, plasma antioxidant concentrations, and chemotherapy-induced toxicity. This study was conducted to investigate the effect of therapy on antioxidant intakes in children with acute lymphoblastic leukemia, the relation between dietary antioxidant intakes and plasma antioxidant concentrations, and the relation between the incidence of side effects due to treatment and antioxidant intake. We conducted a 6-mo observational study of 103 children with acute lymphoblastic leukemia. Plasma micronutrient concentrations, dietary intakes, and incidence of side effects of chemotherapy were ascertained at diagnosis and after 3 and 6 mo of therapy. Throughout the 6-mo study period, subjects ingested vitamin E, total carotenoid, beta-carotene, and vitamin A in amounts that were 66%, 30%, 59%, and 29%, respectively, of the US recommended dietary allowance or of the amounts specified in the third National Health and Nutrition Examination Survey. Greater vitamin C intakes at 6 mo were associated with fewer therapy delays, less toxicity, and fewer days spent in the hospital. Greater vitamin E intakes at 3 mo were associated with a lower incidence of infection. Greater beta-carotene intakes at 6 mo were associated with a decreased risk of toxicity. A large percentage of children undergoing treatment for acute lymphoblastic leukemia have inadequate intakes of antioxidants and vitamin A. Lower intakes of antioxidants are associated with increases in the adverse side effects of chemotherapy.


A Machine Learning Approach for the Identification of a Biomarker of Human Pain using fNIRS.
Pain is a highly unpleasant sensory and emotional experience, and no objective diagnosis test exists to assess it. In clinical practice there are two main methods for the estimation of pain, a patient's self-report and clinical judgement. However, these methods are highly subjective and the need of biomarkers to measure pain is important to improve pain management, reduce risk factors, and contribute to a more objective, valid, and reliable diagnosis. Therefore, in this study we propose the use of functional near-infrared spectroscopy (fNIRS) and machine learning for the identification of a possible biomarker of pain. We collected pain information from 18 volunteers using the thermal test of the quantitative sensory testing (QST) protocol, according to temperature level (cold and hot) and pain intensity (low and high). Feature extraction was completed in three different domains (time, frequency, and wavelet), and a total of 69 features were obtained. Feature selection was carried out according to three criteria, information gain (IG), joint mutual information (JMI), and Chi-squared (χ2). The significance of each feature ranking was evaluated using three learning models separately, linear discriminant analysis (LDA), the K-nearest neighbour (K-NN) and support vector machines (SVM) using the linear and Gaussian and polynomial kernels. The results showed that the Gaussian SVM presented the highest accuracy (94.17%) using only 25 features to identify the four types of pain in our database. In addition, we propose the use of the top 13 features according to the JMI criteria, which exhibited an accuracy of 89.44%, as promising biomarker of pain. This study contributes to the idea of developing an objective assessment of pain and proposes a potential biomarker of human pain using fNIRS.


"Is the doctor God to punish me?!" An intersectional examination of disrespectful and abusive care during childbirth against single mothers in Tunisia.
Disrespectful and abusive treatment during childbirth is a violation of women's right to dignified, respectful healthcare throughout pregnancy and childbirth. Although reports point out that marginalized groups in society such as single mothers are particularly vulnerable to abusive and disrespectful care, there is a lack of in-depth research exploring single mothers' encounters at the maternal healthcare facilities, especially in Tunisia. In Tunisia, single mothers are particularly vulnerable due to their social stigmatization and socio-economic marginalization. This study examines the self-perceptions and childbirth experiences of single mothers at the public healthcare facilities in Tunisia. This study follows a qualitative design. Eleven single mothers were interviewed in regard to their experiences with maternal healthcare services and their perceptions of the attitudes of the health workers towards them. The interviews also addressed the barriers faced by the participants in accessing adequate maternal healthcare services, and their self-perceptions as single mothers. The data were analyzed using an inductive thematic approach guided by the feminist intersectional approach. Emergent codes were grouped into three final themes. Three themes emerged during the data analysis: 1) Experiencing disrespect and abuse, 2) Perceptions of regret and shame attributed to being a single mother, and 3) The triad of vulnerability: stigma, social challenges, and health system challenges. The study highlights that the childbirth experiences of single mothers are shaped by intersectional factors that go beyond the health system. Gender plays a major role in constructing these experiences while intersecting with other social structures. The participants had experienced disrespectful and discriminatory practices and even violence when they sought maternal healthcare services at the public healthcare facilities in Tunisia. Those experiences reflect not only the poor quality of maternal health services but also how health system practices translate the stigma culturally associated with single motherhood in this setting. Social stigma did not only affect how single mothers were treated during the childbirth, but also how they perceived themselves and how they perceived their care. Ensuring women's right to dignified, respectful healthcare during childbirth requires tackling the underlying causes of social inequalities leading to women's marginalization and discrimination.


Detecting gene duplications in the human lineage.
Gene duplications represent an important class of evolutionary events that is likely to have contributed to the unique human phenotype in the short evolutionary time since the human-chimpanzee divergence. With the availability of both human and chimpanzee genome drafts in high coverage re-sequencing assemblies and the high annotation quality of most human genes, it should now be possible to identify all human lineage-specific gene duplication events (human inparalogues) and a few pioneering studies have attempted to do that. However, the different levels of coverage in the human and chimpanzee's genomes assemblies, and the differing levels of gene annotation, have led to problematic assumptions and oversimplifications in the algorithms and the datasets used to detect human lineage-specific gene duplications. In this study, we have developed a set of bioinformatic tools to overcome a number of the conceptual problems that are prevalent in previous studies and have collected a reliable and representative set of human inparalogues.


Pisat's Visual Vasopressor Injection Needle: An Innovative Tool for Increasing Patient Safety in Laparoscopic Myomectomy.
The use of vasopressin and other vasoconstrictive agents to reduce blood loss during laparoscopic myomectomy significantly reduces blood loss and operative time. However, serious cardiovascular complications following the use of intramyometrial injection of vasopressin solution have also been reported. Most of these side effects are believed to be due to inadvertent intravascular injection of vasopressin solution. To describe a new design of an injection needle. Pisat's visual vasopressor injection needle (VVIN) can be used during laparoscopic myomectomy to minimise the incidence of an inadvertent intravascular injection of a vasoconstrictor solution. A total of 53 patients who underwent laparoscopic myomectomy at various hospitals in Mumbai, India were studied over a period of two years. Out of these, 23 patients were operated upon using a standard 5 mm laparoscopic injection needle, and 30 patients were operated on by using a VVIN. Out of the 23 patients in whom a regular needle was used, four patients (17.39%) demonstrated a significant (over 20% of pre-injection value), but transient, elevation in pulse and blood pressure readings at one minute post injection. This gradually returned to baseline at 10 minutes after the injection. None of the 30 patients in whom VVIN was used after confirming a negative aspiration demonstrated any significant change in post-injection pulse or blood pressure recordings. Using a VVIN during a laparoscopic myomectomy enables the surgeon to detect an inadvertent vascular puncture very early, even in a small calibre blood vessel, and with much more sensitivity than a regular needle. This increases patient safety during the intramyometrial injection of a vasoconstrictive agent during myomectomy and reduces the incidence of catastrophic complications.


Rational Design of Evolutionarily Stable Microbial Kill Switches.
The evolutionary stability of synthetic genetic circuits is key to both the understanding and application of genetic control elements. One useful but challenging situation is a switch between life and death depending on environment. Here are presented "essentializer" and "cryodeath" circuits, which act as kill switches in Escherichia coli. The essentializer element induces cell death upon the loss of a bi-stable cI/Cro memory switch. Cryodeath makes use of a cold-inducible promoter to express a toxin. We employ rational design and a toxin/antitoxin titering approach to produce and screen a small library of potential constructs, in order to select for constructs that are evolutionarily stable. Both kill switches were shown to maintain functionality in vitro for at least 140 generations. Additionally, cryodeath was shown to control the growth environment of a population, with an escape frequency of less than 1 in 105 after 10 days of growth in the mammalian gut.


Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4DCAF1 to suppress oncogenic gene expression.
Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain-containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL4(DCAF1) to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL4(DCAF1) and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).


Testosterone causes direct relaxation of rat thoracic aorta.
Several recent studies have provided evidence that gonadal steroid hormones can exert acute (nongenomic) effects on both neural and vascular tissues. This study examines the acute effects of testosterone (T) on vascular reactivity of the rat thoracic aorta. Aortic rings from male Sprague-Dawley (SD) rats with (+ENDO) and without (-ENDO) endothelium were prepared for isometric tension recording. In (+ENDO) male aortae precontracted with phenylephrine (PE), T produced dose-dependent relaxation from 25 microM (30.3 +/- 7.1%) to 300 microM (99.4 +/- 0.4%), whereas T vehicle (< or = 0.5% ethanol) had no effect. Pretreatment of (+ENDO) aortae with T (50 microM; 10 min) attenuated subsequent contractile responses to PE. Both maximal contraction and sensitivity to PE were reduced by T. Pretreatment of (+ENDO) aortae with both T and N omega-nitro-L-arginine methyl ester (250 microM) reversed in part the attenuating effects of T alone; however, both maximal response and sensitivity to PE were still reduced compared to control rings (without T or N omega-nitro-L-arginine methyl ester). Pretreatment of (-ENDO) aortae with T reduced sensitivity to PE, but had no effect on maximal contraction. T pretreatment (50 microM; 10 min) of both (+ENDO) female SD aortae and (+ENDO) male testicular-feminized rat aortae reduced maximal contraction and sensitivity to PE in both groups to a similar extent as in (+ENDO) male SD aortae. These data suggest that T has a direct vasodilating effect on the rat aorta, which involves endothelium-dependent (enhanced NO release) and -independent mechanisms and is gender- and intracellular androgen receptor-independent.


The intracellular distribution and heterogeneity of ribonucleic acid in starfish oocytes.
A study has been made of the content and composition of RNA in cytoplasm, nucleoplasm, and nucleoli from growing oocytes of the starfish Asterias rubens. The determinations were carried out, using ultramicrochemical methods, on units isolated by microdissection from fixed sections. Macrochemical and interferometric control experiments show that RNA can be quantitatively evaluated in this way. The results show that the growing oocyte represents a system in which the relations between the quantities of nucleolar, nucleoplasmic, and cytoplasmic RNA undergo great changes. These changes are continuous for nucleolar and cytoplasmic RNA so that their amounts may be predicted from the size of the cell. Nucleoplasmic RNA, on the other hand, shows great variations among different cells, independent of cell size. Purine-pyrimidine analyses show that each cell component contains an RNA which differs significantly from that of the other two. Cytoplasmic and nucleolar RNA are closely related, the only difference being a slightly higher guanine/uracil quotient for the nucleolar RNA. They are both of the usual tissue RNA type, i.e., they show a preponderance of guanine and cytosine over adenine and uracil. Nucleoplasmic RNA deviates grossly from the RNA of the other two components. Here the concentrations of adenine and uracil are higher than those of guanine and cytosine, respectively. This RNA consequently shows some resemblance to the general type of animal DNA although the purine/pyrimidine ratio is far from unity. Our data favor a nucleolar origin for the stable part of the ribosomal RNA and a nucleoplasmic one for the unstable part (the messenger RNA).


Quality Improvement Project to Decrease Delivery Room Intubations in Preterm Infants.
Avoidance of delivery room intubation (DRI) reduces death or bronchopulmonary dysplasia (BPD) in preterm neonates. Our objective with this quality improvement project was to decrease DRI rates by improving face mask positive pressure ventilation (Fm-PPV) among infants born ≤29 weeks' gestation. Key drivers of change were identified from a retrospective review of resuscitation records. A resuscitation bundle to optimize Fm-PPV including the use of a small round mask and end-tidal CO2 detectors, increasing peak inspiratory pressure when indicated, and debriefing after each intubation were implemented in consecutive plan-do-study-act cycles. The DRI rate was tracked by using a control chart. Resuscitation practice and outcomes of pre-quality improvement cohort (QIC) (January 2014-September 2015) were compared with post-QIC (October 2015-December 2016). Of the 314 infants who were resuscitated, 180 belonged to the pre-QIC and 134 to the post-QIC. The antenatal steroid administration rate was higher in the post-QIC (54% vs 88%). More infants in the post-QIC had resolution of bradycardia after Fm-PPV (56% vs 77%, P = .02). Infants in the post-QIC had lower DRI rates (58% vs 37%, P < .01), lower need for mechanical ventilation (85% vs 70%, P < .01), lower rates of BPD (26% vs 13%, P < .01), and severe retinopathy of prematurity (14% vs 5%, P = .01). Rates of DRI, BPD, and severe retinopathy of prematurity remained lower even after controlling for the potential confounders. Implementation of a resuscitation bundle decreased the DRI rate and improved outcomes of preterm infants.


Context-dependent judgments of color that might allow color constancy in scenes with multiple regions of illumination.
For a color-constant observer, a change in the spectral composition of the illumination is accompanied by a corresponding change in the chromaticity associated with an achromatic percept. However, maintaining color constancy for different regions of illumination within a scene implies the maintenance of multiple perceptual references. We investigated the features of a scene that enable the maintenance of separate perceptual references for two displaced but overlapping chromaticity distributions. The time-averaged, retinotopically localized stimulus was the primary determinant of color appearance judgments. However, spatial separation of test samples additionally served as a symbolic cue that allowed observers to maintain two separate perceptual references.


Risk of obesity in immigrants compared with Swedes in two deprived neighbourhoods.
Despite a strong social gradient in the prevalence of obesity, there is little scientific understanding of obesity in people settled in deprived neighbourhoods. Few studies are actually based on objectively measured data using random sampling of residents in deprived neighbourhoods. In addition, most studies use a crude measure, the body mass index, to estimate obesity. This is of concern because it may cause inaccurate estimations of the true prevalence and give the wrong picture of the factors associated with obesity. The aim of this study was to estimate the prevalence of, and analyse the sociodemographic factors associated with, three indices of obesity in different ethnic groups settled in two deprived neighbourhoods in Sweden. Height and weight, waist circumference and body fat percentage were objectively measured in a random sample (n = 289). Sociodemographic data were obtained through a survey. Established cut-offs were used to determine obesity. Country of birth was categorized as Swedish, Other European, and Middle Eastern. Odds ratios were estimated by unconditional logistic regression. One third of the sample was classified as obese overall, with 39.0% of women being abdominally obese. After adjusting for age, we found higher odds of obesity in Middle Eastern women than in Swedish women regardless of outcome with odds ratios ranging between 2.74 and 5.53. Men of other European origin had higher odds of BMI obesity than Swedish men. Most associations between country of birth and obesity remained in the full model. This study demonstrates the magnitude of the obesity problem and the need for prevention programmes targeting native and immigrant adults in deprived neighbourhoods in Sweden. The initiatives should also focus on particular groups, e.g. immigrant women and those experiencing economic difficulties. Further studies are needed on behavioural and environmental factors influencing the risk of obesity in residents settled in deprived neighbourhoods.


[Characteristics of the aggregative state of the substrate in the reaction of 5-lipoxygenase oxidation of linoleic acid].
5-lipoxygenase (EC 126.96.36.199) oxidizes polyunsaturated fatty acids by molecular oxygen. The enzyme acts in close contact with the cell membranes, which main components are ionic and non-ionic lipids. In order to investigate the kinetic parameters of 5-lipoxygenase reaction in vitro, extremely hydrophobic fatty acid substrate (linoleic acid) should be solubilized in the reaction mixture. We used Lubrol PX ("Sigma" Chem. Co), as a non-ionic detergent consisted of oligoethylene glycol and fatty alcohol. Linoleic acid and Lubrol PX formed mixed micelles thus solubilizing the fatty acid substrate in a buffer with appropriate pH. We have studied the sizes and shapes of mixed micelles Lubrol PX/linoleic acid (aggregates type 1) and Lubrol PX/linoleic acid/SDS (aggregates type 2; SDS was an effective activator of potato tuber 5-lipoxygenase) by means of gel-filtration and laser light scattering techniques. The parameters under investigation were molecular weights, Stocks radii and shapes of the mixed micelles. The average molecular weights and Stocks radii of the mixed micelles type 1 determined by mean of gel-filtration on Sephadex G-200 were 95,142 +/- 5184 Da and 3.45 +/- 0.11 nm, respectively. The same parameters for the mixed micelles type 2 were 73,694 +/- 893 Da and 3.02 +/- 0.02 nm, respectively. The strong similarity in physicochemical parameters for both types of mixed micelles indicated that SDS did not influence the size and shape of mixed micelles of Lubrol PX and linoleic acid. The activatory action of SDS on potato tuber lipoxygenase may be a result of electrostatic effect or direct participation of SDS in enzymatic catalysis. The laser light scattering technique allowed to determine two main fraction of particles in type 1 system with hydrodynamic diameters 2.6 and 5.7 nm and relative contribution to light scattering 13 and 87%, respectively. The particles with d = 5.7 nm were interpreted as the mixed micelles. The particles with d = 2.6 nm were interpreted as isolated molecules of Lubrol PX, linoleic acid and (or) their premicellar aggregates. The data obtained are to be used in creation of reliable physical and mathematical models of 5-lipoxygenase.


Variations in Oncologist Recommendations for Chemotherapy for Stage IV Lung Cancer: What Is the Role of Performance Status?
Chemotherapy prolongs survival in patients with advanced non-small-cell lung cancer. However, few studies have included patients with poor performance status. This study examined rates of oncologists' recommendations for chemotherapy by patient performance status and symptoms and how physician characteristics influence chemotherapy recommendations. We surveyed medical oncologists involved in the care of a population-based cohort of patients with lung cancer from the CanCORS (Cancer Care Outcomes Research and Surveillance) study. Physicians were queried about their likelihood to recommend chemotherapy to patients with stage IV lung cancer with varying performance status (Eastern Cooperative Oncology Group performance status 0 [good] v 3 [poor]) and presence or absence of tumor-related pain. Repeated measures logistic regression was used to estimate the independent associations of patients' performance status and symptoms and physicians' demographic and practice characteristics with chemotherapy recommendations. Nearly all physicians (adjusted rate, 97% to 99%) recommended chemotherapy for patients with good performance status, and approximately half (adjusted rate, 38% to 53%) recommended chemotherapy for patients with poor performance status (P < .001). Compared with patient factors, physician and practice characteristics were less strongly associated with chemotherapy recommendations in adjusted analyses. Strong consensus among oncologists exists for chemotherapy in patients with advanced non-small-cell lung cancer and good performance status. However, the relatively high rate of chemotherapy recommendations for patients with poor performance status despite the unfavorable risk-benefit profile highlights the need for ongoing work to define high-value care in oncology and to implement and evaluate strategies to align incentives for such care.


Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients.
Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching. clinicaltrials.gov number: NCT04388670.


Genetical genomics: use all data.
Genetical genomics is a very powerful tool to elucidate the basis of complex traits and disease susceptibility. Despite its relevance, however, statistical modeling of expression quantitative trait loci (eQTL) has not received the attention it deserves. Based on two reasonable assertions (i) a good model should consider all available variables as potential effects, and (ii) gene expressions are highly interconnected, we suggest that an eQTL model should consider the rest of expression levels as potential regressors, in addition to the markers. It is shown that power can be increased with this strategy. We also show, using classical statistical and support vector machines techniques in a reanalysis of public data, that the external transcripts, i.e., transcripts other than the one being analysed, explain on average much more variability than the markers themselves. The presence of eQTL hotspots is reassessed in the light of these results. Model choice is a critical yet neglected issue in genetical genomics studies. Although we are far from having a general strategy for model choice in this area, we can at least propose that any transcript level is scanned not only for the markers genotyped but also for the rest of gene expression levels. Some sort of stepwise regression strategy can be used to select the final model.


Novel multi-analyte responsive ionic supramolecular gels based on pyridinium functionalized-naphthalimide.
A novel ionic supramolecular gel (is-G) is synthesized using N-(pyridinium-4-yl)-naphthalimide (G1) and n-pentanoic acid. By rationally introducing competitive coordination into is-G, two ion coordinated ionic supramolecular gels is-IG and is-FeG (coordinated with I- and Fe3+, respectively) are obtained. is-IG could fluorescently "turn-on" detect Hg2+ and l-Arg with specific selectivity, whereas, is-FeG could accurately identify l-Ser via fluorescence in water. Moreover, ion or amino acid responsive films based on these ionic supramolecular gels are prepared. These ionic supramolecular gels and films could act as multi-analyte detection materials as well as fluorescent display materials.


Child health and nutrition in Peru within an antipoverty political agenda: a Countdown to 2015 country case study.
Peru is an upper-middle-income country with wide social and regional disparities. In recent years, sustained multisectoral antipoverty programmes involving governments, political parties, and civil society have included explicit health and nutrition goals and spending increased sharply. We did a country case study with the aim of documenting Peru's progress in reproductive, maternal, neonatal, and child health from 2000-13, and explored the potential determinants. We examined the outcomes of health interventions coverage, under-5 mortality, neonatal mortality, and prevalence of under-5 stunting. We obtained data from interviews with key informants, a literature review of published and unpublished data, national censuses, and governmental reports. We obtained information on social determinants of health, including economic growth, poverty, unmet basic needs, urbanisation, women's education, water supply, fertility rates, and child nutrition from the annual national households surveys and the Peruvian Demographic and Health Surveys. We obtained national mortality data from the Interagency Group for Child Mortality Estimation, and calculated subnational rates from 11 surveys. Analyses were stratified by region, wealth quintiles, and urban or rural residence. We calculated coverage indicators for the years 2000-13, and we used the Lives Saved Tool (LiST) to estimate the effect of changes in intervention coverage and in nutritional status on mortality. From 2000 to 2013, under-5 mortality fell by 58% from 39·8 deaths per 1000 livebirths to 16·7. LiST, which was used to predict the decline in mortality arising from changes in fertility rates, water and sanitation, undernutrition, and coverage of indicators of reproductive, maternal, neonatal, and child health predicted that the under-5 mortality rate would fall from 39·8 to 28·4 per 1000 livebirths, accounting for 49·2% of the reported reduction. Neonatal mortality fell by 51% from 16·2 deaths per 1000 livebirths to 8·0. Stunting prevalence remained stable at around 30% until 2007, decreasing to 17·5% by 2013, and the composite coverage index for essential health interventions increased from 75·1% to 82·6%, with faster increases among the poor, in rural areas, and in the Andean region. Socioeconomic, urban-rural, and regional inequalities in coverage, mortality, and stunting were substantially reduced. The proportion of the population living below the poverty line reduced from 47·8% to 23·9%, women with fewer than 4 years of schooling reduced from 11·5% to 6·9%, urbanisation increased from 68·1% to 75·6%, and the total fertility rate decreased from 3·0 children per woman to 2·4. We interviewed 175 key informants and they raised the following issues: economic growth, improvement of social determinants, civil society empowerment and advocacy, out-of-health and within-health-sector changes, and sustained implementation of evidence-based, pro-poor reproductive, maternal, neonatal, and child health interventions. Peru has made substantial progress in reducing neonatal and under-5 mortality, and child stunting. This country is a good example of how a combination of political will, economic growth, broad societal participation, strategies focused on poor people, and increased spending in health and related sectors can achieve significant progress in reproductive, maternal, neonatal, and child health. The remaining challenges include continuing to address inequalities in wealth distribution, poverty, and access to basic services, especially in the Amazon and Andean rural areas. Bill & Melinda Gates Foundation.


c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology.
Adhesive and locomotive properties of cells have key roles in normal physiology and disease. Cell motility and adhesion require the assembly and organization of actin microfilaments into stress fibers, lamellipodia and filopodia, and the formation of these structures is mediated by signalling through Rho; GTPases. Here we identify c-Cbl (a multi-adaptor proto-oncogene product involved in protein tyrosine kinase signalling) as an important regulator of the actin cytoskeleton. By immunofluorescence microscopy we have determined that c-Cbl co-localizes with the adaptor protein Crk to submembranous actin lamellae in NIH 3T3 fibroblasts and that c-Cbl's actin localization requires specific SH3-binding sequences. Further, we have found that truncation of this SH3-binding domain in c-Cbl profoundly alters the morphology of NIH 3T3 fibroblasts by inhibiting the formation of actin lamellae, lamellipodia and membrane ruffles. The induction of lamellipodia and membrane ruffles are also inhibited during cell spreading and migration, conditions when these structures are normally most prominent. The inhibitory effect of truncated c-Cbl expression on lamellipodia formation can be reversed by mutational inactivation of its divergent SH2 domain, by the co-expression of constitutively active Rac or by the overexpression of c-Cbl. This study therefore identifies a cytoskeletal role for c-Cbl which may involve the regulation of Crk and Rac, and which is dependent on targeting of c-Cbl to actin lamellae and the ability to recruit signalling protein(s) associated with its divergent SH2 domain.


The electronic nose: emerging biomarkers in lung cancer diagnostics.
Lung cancer is very common and the most common cause of cancer death worldwide. Despite recent progress in the systemic treatment of lung cancer (checkpoint inhibitors and tyrosine kinase inhibitors), each year, >1.5 million people die due to this disease. Most lung cancer patients already have advanced disease at the time of diagnosis. Computed tomography screening of high-risk individuals can detect lung cancer at an earlier stage but at a cost of false-positive findings. Biomarkers could lead towards a reduction of these false-positive findings and earlier lung cancer diagnosis, and have the potential to improve outcomes and treatment monitoring. To date, there is a lack of such biomarkers for lung cancer and other thoracic malignancies, although electronic nose (e-nose)-derived biomarkers are of interest. E-nose techniques using exhaled breath component measurements can detect lung cancer with a sensitivity ranging from 71% to 96% and specificity from 33 to 100%. In some case series, such results have been validated but this is mostly using internal validation and hence, more work is needed. Furthermore, standardised sampling and analysis methods are lacking, impeding interstudy comparison and clinical implementation. In this narrative review, we provide an overview of the currently available data on E-nose technology for lung cancer detection.


Deciphering the Roles of N-Glycans on Collagen-Platelet Interactions.
Collagen is a potent agonist for platelet activation, presenting itself as a key contributor to coagulation via interactions with platelet glycoproteins. The fine details dictating platelet-collagen interactions are poorly understood. In particular, glycosylation could be a key determinant in the platelet-collagen interaction. Here, we report an affinity purification coupled to a mass spectrometry-based approach to elucidate the function of N-glycans in dictating platelet-collagen interactions. By integrative proteomic and glycoproteomic analysis of collagen-platelet interactive proteins with N-glycan manipulation, we demonstrate that the interaction of platelet adhesive receptors with collagen is highly N-glycan regulated, with glycans on many receptors playing positive roles in collagen binding, with glycans on other platelet glycoproteins exhibiting inhibitory roles on the binding to collagen. Our results significantly enhance our understanding of the details of glycans influencing the platelet-collagen interaction.


Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues.
Inflammation has been strongly implicated in prostate carcinogenesis, but the precise molecular mechanisms linking inflammation and carcinogenic DNA damage are not known. Induction of the polyamine catabolic enzyme, spermine oxidase (SMO) has been linked to increased reactive oxygen species (ROS) and DNA damage in human gastric and lung epithelial cells and suggest direct mechanistic links between inflammation, SMO activity, ROS production, and epithelial carcinogenesis that are likely relevant in prostate cancer. Tissue microarrays consisting of matched normal and diseased specimens from patients diagnosed with prostate cancer, prostatic intraepithelial neoplasia (PIN), or proliferative inflammatory atrophy (PIA), as well as unaffected individuals, were stained for SMO expression and analyzed using image analysis techniques and TMAJ software tools. Average SMO staining was significantly higher in prostate cancer and PIN tissues compared to patient-matched benign tissues. Benign tissues from prostate cancer, PIN, and PIA patients also exhibited significantly higher mean SMO expression versus tissues from prostate disease-free patients. Tissues from patients diagnosed with prostate cancer and PIN exhibit, on average, locally increased SMO expression in regions of prostatic disease and higher overall SMO expression in prostatic epithelial cells compared to healthy individuals. Further studies are warranted to directly examine the role of SMO-produced ROS in prostate carcinogenesis.


Impaired beta-endorphin response to human corticotropin-releasing hormone in obese children.
In order to evaluate the secretion of beta-endorphin in obese children and adolescents, we measured plasma beta-endorphin, ACTH and cortisol levels before and following administration of CRH (1 microgram/kg). Fourteen normal weight and 22 obese subjects (weight excess ranging from 30 to 98%) were studied. Plasma hormone levels were measured by radioimmunoassay directly in plasma (cortisol, ACTH) and after silicic acid extraction and Sephadex G-75 column chromatography (beta-endorphin). Basal beta-endorphin levels in obese children were significantly higher than in controls (14.7 +/- 1.8 vs 6.0 +/- 0.6 pmol/l; mean +/- SEM). No differences were found in basal ACTH and cortisol levels. CRH administration significantly increased beta-endorphin, ACTH and cortisol levels in normal subjects and ACTH and cortisol levels in obese subjects. Plasma beta-endorphin levels in obese children and adolescents did not show any significant increment. These data confirm the higher than normal beta-endorphin plasma levels in obese subjects in childhood and demonstrate that CRH is unable to increase beta-endorphin levels, suggesting an impairment of the hypothalamo-pituitary control mechanisms or an extra-anterior pituitary source.


TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes.
Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism. To map the expression of TCF7L2 in human AT, examine its role in human adipose cell biology in vitro, and investigate the effects of the fine-mapped T2D-risk allele at rs7903146 on AT morphology and TCF7L2 expression. Ex vivo gene expression studies of TCF7L2 in whole and fractionated human AT. In vitro TCF7L2 gain- and/or loss-of-function studies in primary and immortalized human adipose progenitor cells (APCs) and mature adipocytes (mADs). AT phenotyping of rs7903146 T2D-risk variant carriers and matched controls. Adipose progenitors (APs) exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in whole subcutaneous abdominal AT but paradoxically increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in abdominal APs led to dose-dependent activation of WNT/β-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, near-total KD impaired lipid accumulation and adipogenic gene expression. Over-expression of TCF7L2 accelerated adipogenesis. In contrast, TCF7L2-KD in gluteal APs dose-dependently enhanced lipid accumulation. Transcriptome-wide profiling revealed that TCF7L2 might modulate multiple aspects of AP biology including extracellular matrix secretion, immune signaling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity. TCF7L2 plays a complex role in AP biology and has both dose- and depot-dependent effects on adipogenesis. In addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 might also influence T2D risk by modulating AP function.


Lowering of glucose in critical care: a randomized pilot trial.
Similar to cardiac surgery patients, medical-surgical critically ill patients may benefit from intensive insulin therapy. The objectives of this pilot trial were to evaluate the feasibility of a randomized trial of intensive insulin therapy with respect to (a) achieving target glucose values in the 2 ranges of 5 to 7 and 8 to 10 mmol/L and (b) uncovering problems with the protocol in anticipation of a larger trial. The trial was conducted in a 15-bed medical-surgical university-affiliated intensive care unit (ICU). We included patients older than 18 years, expected to be in ICU for more than 72 hours, with a glucose value of more than 10 mmol/L within 48 hours of ICU admission. Exclusion criteria were diabetic ketoacidosis, severe hepatic failure or hepatic resection, pancreatitis, glucose of less than 2.2 mmol/L on admission to hospital, insulin infusion on admission to ICU, planned withdrawal of life support, and inability to obtain informed consent. Patients underwent concealed random allocation to a target glucose range of 5 to 7 or 8 to 10 mmol/L using pretested algorithms of insulin infusions. Dedicated glucometer measurement of arterial glucose values was calibrated daily to values measured in the laboratory. We enrolled 20 patients with a mean (SD) Acute Physiology and Chronic Health Evaluation (APACHE) II score of 32 (10.2); 14 were insulin-dependent pre-ICU, and all were medical admissions. Mean glucose values were different in the 2 groups (7.1 +/- 2.6 vs 9.4 +/- 2.1 mmol/L, P < .001). Although the intensive insulin therapy group had more glucose measurements performed than the control group, a similar proportion of values were within the target range (682 [42.4%] of 1607 values in the 5- to 7-mmol/L range; 250 [38.7%] of 660 values in the 8- to 10-mmol/L range, P = .35). Glucose values of less than 2.5 mmol/L developed 7 times in 5 patients, 4 of whom were in the intensive insulin therapy group; however, no adverse consequences were documented. As expected, there were no differences in clinically important outcomes. In this pilot trial of ICU patients with high illness severity, glucose values were in the 2 target ranges only 40% of the time, using well-accepted initiation and maintenance insulin infusion algorithms. A large randomized trial of glycemic control is feasible in this population to examine clinically important outcomes, but will require refined insulin algorithms and more comprehensive behavior change strategies to achieve target values.


Clostridium difficile infection in the Lao People's Democratic Republic: first isolation and review of the literature.
Current knowledge of the epidemiology of Clostridium difficile infection in Asia, and in particular the Greater Mekong Subregion, is very limited. Only a few studies from Thailand and Vietnam have been reported from the region with variable testing methods and results, and no studies from Lao People's Democratic Republic (PDR). Therefore we investigated the presence of C. difficile in a single centre in the Lao PDR and determined the ribotypes present. Seventy unformed stool samples from hospital inpatients at Mahosot Hospital, Vientiane, were tested for the presence of C. difficile using selective differential agar and confirmed by latex agglutination. C. difficile isolates were further characterised by ribotyping and toxin gene detection. C. difficile was isolated from five of the 70 patients, and five different ribotypes were identified (014, 017, 020, QX 107 and QX 574). This is the first isolation of C. difficile from human stool samples in the Lao PDR. These results will add to the limited amount of data on C. difficile in the region. In addition, we hope this information will alert clinicians to the presence of C. difficile in the country and will help inform future investigations into the epidemiology and diagnosis of C. difficile in Lao PDR.


Metacognitive asymmetries in visual perception.
People have better metacognitive sensitivity for decisions about the presence compared to the absence of objects. However, it is not only objects themselves that can be present or absent, but also parts of objects and other visual features. Asymmetries in visual search indicate that a disadvantage for representing absence may operate at these levels as well. Furthermore, a processing advantage for surprising signals suggests that a presence/absence asymmetry may be explained by absence being passively represented as a default state, and presence as a default-violating surprise. It is unknown whether the metacognitive asymmetry for judgments about presence and absence extends to these different levels of representation (object, feature, and default violation). To address this question and test for a link between the representation of absence and default reasoning more generally, here we measure metacognitive sensitivity for discrimination judgments between stimuli that are identical except for the presence or absence of a distinguishing feature, and for stimuli that differ in their compliance with an expected default state.


In the spotlight: healthcare inspections as an opportunity for trainee clinicians to be the leaders of today.
There have been repeated calls from all quarters of healthcare for more clinicians to be leaders. The risks of not accepting this responsibility have been demonstrated by harrowing reports into failed care in England. Ambiguity persists over what clinical leadership encompasses, how it can be developed and how to inspire clinicians to practise it. A supportive organisational culture, dedicated resources and national support are needed to foster leadership skills among trainee clinicians. Here we discuss a possible blueprint based on the recent reviews of English NHS Trusts with high mortality rates for future initiatives in empowering medical and nursing trainees to learn from leaders and practise leadership skills.


IL-10-producing T cells suppress immune responses in anergic tuberculosis patients.
The lethality of Mycobacterium tuberculosis remains the highest among infectious organisms and is linked to inadequate immune response of the host. Containment and cure of tuberculosis requires an effective cell-mediated immune response, and the absence, during active tuberculosis infection, of delayed-type hypersensitivity (DTH) responses to mycobacterial antigens, defined as anergy, is associated with poor clinical outcome. To investigate the biochemical events associated with this anergy, we screened 206 patients with pulmonary tuberculosis and identified anergic patients by their lack of dermal reactivity to tuberculin purified protein derivative (PPD). In vitro stimulation of T cells with PPD induced production of IL-10, IFN-gamma, and proliferation in PPD(+) patients, whereas cells from anergic patients produced IL-10 but not IFN-gamma and failed to proliferate in response to this treatment. Moreover, in anergic patients IL-10-producing T cells were constitutively present, and T-cell receptor-mediated (TCR-mediated) stimulation resulted in defective phosphorylation of TCRzeta and defective activation of ZAP-70 and MAPK. These results show that T-cell anergy can be induced by antigen in vivo in the intact human host and provide new insights into mechanisms by which M. tuberculosis escapes immune surveillance.


Degenerative spondylolisthesis of the cervical spine: analysis of 58 patients treated with anterior cervical decompression and fusion.
Degenerative spondylolisthesis has been well described as a disorder of the lumbar spine. Few authors have suggested that a similar disorder occurs in the cervical spine. To our knowledge, the present study represents the largest series of patients with long-term follow-up who were managed surgically for the treatment of degenerative spondylolisthesis of the cervical spine. To describe the clinical presentation and radiographic findings associated with degenerative cervical spondylolisthesis, and to report the long-term results of surgically managed patients. Analysis of 58 patients treated with anterior cervical decompression and fusion for degenerative spondylolisthesis of the cervical spine. From 1974 to 2003, 58 patients were identified as having degenerative spondylolisthesis of the cervical spine occurring in the absence of trauma, systemic inflammatory arthropathy, or congenital abnormality. These patients were identified from a database of approximately 500 patients with degenerative cervical spine disorders treated by the senior one of us. Patient outcomes were evaluated with regard to neurologic improvement (Nurick grade myelopathy) and osseous fusion. The records of 58 patients were reviewed. The average follow-up period was 6.9 years (range, 2-24 years). Seventy-two cervical levels demonstrated spondylolisthesis. In all cases, there was radiographic evidence of facet degeneration and subluxation. All patients were treated with anterior cervical decompression and arthrodesis with iliac crest structural graft. This most commonly involved corpectomy of the caudal vertebrae. Three patients required additional posterior facet fusion. Fifty-eight patients demonstrated 72 levels of involvement. The C4-C5 level was most frequently involved (43%). Two radiographically distinct types of listhesis were observed based on the amount of disc degeneration and the degree of spondylosis at adjacent levels. The average neurologic improvement was 1.5 Nurick grades. The overall fusion rate was 92%. Three patients were treated with combined anterior-posterior arthrodesis. The prevalence of myelopathy and instability pattern was greater in the listheses occurring adjacent to spondylotic levels. Degenerative spondylolisthesis is relatively common in the cervical spine. Common to all cases is facet arthropathy and neurologic compression. Anterior cervical decompression and arthrodesis appears to yield excellent union rates and neurological improvement in those patients having cervical degenerative spondylolisthesis and significant neurological sequelae who have failed nonoperative treatments.


Micro-ribonucleic acid-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia.
Micro-ribonucleic acid-155 (miR-155) is one of the first described oncogenic miRNAs. Although multiple direct targets of miR-155 have been identified, it is not clear how it contributes to the pathogenesis of acute myeloid leukemia. We found miR-155 to be a direct target of Meis1 in murine Hoxa9/Meis1 induced acute myeloid leukemia. The additional overexpression of miR-155 accelerated the formation of acute myeloid leukemia in Hoxa9 as well as in Hoxa9/Meis1 cells in vivo However, in the absence or following the removal of miR-155, leukemia onset and progression were unaffected. Although miR-155 accelerated growth and homing in addition to impairing differentiation, our data underscore the pathophysiological relevance of miR-155 as an accelerator rather than a driver of leukemogenesis. This further highlights the complexity of the oncogenic program of Meis1 to compensate for the loss of a potent oncogene such as miR-155. These findings are highly relevant to current and developing approaches for targeting miR-155 in acute myeloid leukemia.


'Just in case': the fertility information needs of teenagers and young adults with cancer.
Understanding the reproductive and fertility concerns of teenagers and young adults with cancer (TYA) is one aspect of comprehensive age appropriate care. However, limited options for fertility preservation, coupled with vague policy recommendations, give rise to variations in information-sharing between health care professionals and TYAs, particularly as it involves sensitive discussions regarding the short- and long-term effects of cancer and treatments on fertility and reproduction. This paper presents findings from a wider evaluation at a specialist unit for TYAs with cancer. Forty people participated in semi-structured interviews, including 20 young people, parents and partners. Young people were between 2 months and 4 years from finishing treatment. Most young people received mixed levels of information on fertility and counselling before treatment. Diagnosis in the early teens meant how, and from whom, young people received information varied. Young women tended to receive incomplete information. The majority of young people were unaware of their fertility status after treatment had finished. Findings point to the inherent challenges that exist in ensuring young people aged between 13 and 25 years receive comprehensive information on their fertility and potential risk, as well as advice on how to determine their fertility status after treatment has finished.


Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction.
Environmental exposure to arsenic is linked to adverse health effects, including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation-defective, but not wild-type, SNAP29 into clustered regularly interspaced short palindromic repeat (CRISPR)-mediated SNAP29 knockout cells abolishes arsenic-mediated autophagy inhibition. These findings reveal a mechanism by which low levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic.


Prospective, age-related analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis.
OBJECTIVE To evaluate how age affects functional outcome and quality of life after ileal pouch anal anastomosis (IPAA). SUMMARY BACKGROUND DATA Because of the limited number of older patients undergoing IPAA, it has been difficult to assess functional outcome and quality of life stratified by age. METHODS IPAA was performed in 1895 patients. Patients were stratified by age into <45 (n = 1410), 46-55 (n = 289), 56-65 (n = 154), and more than 65 years (n = 42). Outcome was assessed prospectively. Results are presented at 1, 3, 5, and 10 years after surgery.RESULTS Patients were followed for 4.6 +/- 3.7 years (maximum, 17 years). Pouch failure occurred in 4.1% (pouch excision or permanent diversion). Incontinence and night time seepage were more common in older patients. There were minor differences in the quality of life, health, energy and happiness between age groups, with a slight benefit for those under 45 years. Fourteen percent or fewer patients experienced social, sexual or work restrictions. Overall, 96% of patients were happy to have undergone their surgery, and 98% recommended it to others. Although the respective figures were 89% and 96% in the over-65 age group, the difference was not significant. CONCLUSIONS These data provide a unique assessment of outcome after IPAA at multiple time points. Although functional outcome after IPAA is not as good in older patients, appropriate case selection confers acceptable function and quality of life to patients of all ages.


Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium falciparum: presence of dolichols of 11 and 12 isoprene units.
N-glycosylation of proteins is required for the intra-erythrocytic schizogony of Plasmodium falciparum. In eukaryotic cells, this process involves the transfer of oligosaccharides from a dolichyl pyrophosphate derivative to asparagine residues. We have identified dolichol, dolichyl phosphate and dolichyl pyrophosphate species of 11 and 12 isoprenoid residues by metabolic labelling with [(3)H]farnesyl pyrophosphate, [(3)H]geranylgeranyl pyrophosphate and [(14)C]acetate in the different intra-erythrocytic stages of P. falciparum. This is the first demonstration of short-chain dolichols in the phylum Apicomplexa. The results demonstrate the presence of an active isoprenoid pathway in the intra-erythrocytic stages of P. falciparum. Parasites treated with mevastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, show depressed biosynthesis of dolichol, dolichyl phosphate and isoprenoid pyrophosphate. This effect is observed in all intra-erythrocytic stages of the parasite life cycle, but is most pronounced in the ring stage. N-linked glycosylation of proteins was inhibited in the ring and young-trophozoite stages after mevastatin treatment of parasite cultures. Therefore the isoprenoid pathway may represent a different approach to the development of new anti-malarial drugs.


Ultrathin tunable terahertz absorber based on MEMS-driven metamaterial.
The realization of high-performance tunable absorbers for terahertz frequencies is crucial for advancing applications such as single-pixel imaging and spectroscopy. Based on the strong position sensitivity of metamaterials' electromagnetic response, we combine meta-atoms that support strongly localized modes with suspended flat membranes that can be driven electrostatically. This design maximizes the tunability range for small mechanical displacements of the membranes. We employ a micro-electro-mechanical system technology and successfully fabricate the devices. Our prototype devices are among the best-performing tunable THz absorbers demonstrated to date, with an ultrathin device thickness (~1/50 of the working wavelength), absorption varying between 60% and 80% in the initial state when the membranes remain suspended, and fast switching speed (~27 μs). The absorption is tuned by an applied voltage, with the most marked results achieved when the structure reaches the snap-down state. In this case, the resonance shifts by >200% of the linewidth (14% of the initial resonance frequency), and the absolute absorption modulation measured at the initial resonance can reach 65%. The demonstrated approach can be further optimized and extended to benefit numerous applications in THz technology.


Examining Microstructural White Matter in Active Duty Soldiers with a History of Mild Traumatic Brain Injury and Traumatic Stress.
There is a high comorbidity of posttraumatic stress (PTS) and mild traumatic brain injury (mTBI), with largely overlapping symptomatology, in military service members. To examine white matter integrity associated with PTS and mTBI as assessed using diffusion tensor imaging (DTI). Seventy-four active-duty U.S. soldiers with PTS (n = 16) and PTS with co-morbid history of mTBI (PTS/mTBI; n = 28) were compared to a military control group (n = 30). Participants received a battery of neurocognitive and clinical symptom measures. The number of abnormal DTI values was determined (>2 SDs from the mean of the control group) for fractional anisotropy (FA) and mean diffusivity (MD), and then compared between groups. In addition, mean DTI values from white matter tracts falling into three categories were compared between groups: (i) projection tracts: superior, middle, and inferior cerebellar peduncles, pontine crossing tract, and corticospinal tract; (ii) association tracts: superior longitudinal fasciculus; and (iii) commissure tracts: cingulum bundle (cingulum-cingulate gyrus and cingulum-hippocampus), and corpus callosum. The comorbid PTS/mTBI group had significantly greater traumatic stress, depression, anxiety, and post-concussive symptoms, and they performed worse on neurocognitive testing than those with PTS alone and controls. The groups differed greatly on several clinical variables, but contrary to what we hypothesized, they did not differ greatly on primary and exploratory analytic approaches of hetero-spatial whole brain DTI analyses. The findings suggest that psychological health conditions rather than pathoanatomical changes may be contributing to symptom presentation in this population.


Practical guidelines for do-not-resuscitate orders.
Do-not-resuscitate orders are widely used, but discussions about their use too often take place late in the patient's illness, after the patient is no longer able to participate in the decision. Most patients have discussed resuscitation issues with their family and would like to have a similar discussion with their physician, but only 10 percent of patients have done so. Although few states have laws addressing the use of do-not-resuscitate orders, they are widely held to be legal based on existing legal precedent. To assist patients or their designated surrogate decision-makers, physicians should supply appropriate prognostic information: one-half of all patients survive resuscitation initially, one-third survive for 24 hours and one-eighth survive to leave the hospital. Certain medical conditions, such as metastatic cancer, impaired renal function, sepsis and dependent functional status are associated with a poor outcome. If conflict occurs, properly facilitated family meetings, repeated discussions and ethics committee consultations can be useful. Legal action should remain a last resort.


Septic AKI in ICU patients. diagnosis, pathophysiology, and treatment type, dosing, and timing: a comprehensive review of recent and future developments.
Evidence is accumulating showing that septic acute kidney injury (AKI) is different from non-septic AKI. Specifically, a large body of research points to apoptotic processes underlying septic AKI. Unravelling the complex and intertwined apoptotic and immuno-inflammatory pathways at the cellular level will undoubtedly create new and exciting perspectives for the future development (e.g., caspase inhibition) or refinement (specific vasopressor use) of therapeutic strategies. Shock complicating sepsis may cause more AKI but also will render treatment of this condition in an hemodynamically unstable patient more difficult. Expert opinion, along with the aggregated results of two recent large randomized trials, favors continuous renal replacement therapy (CRRT) as preferential treatment for septic AKI (hemodynamically unstable). It is suggested that this approach might decrease the need for subsequent chronic dialysis. Large-scale introduction of citrate as an anticoagulant most likely will change CRRT management in intensive care units (ICU), because it not only significantly increases filter lifespan but also better preserves filter porosity. A possible role of citrate in reducing mortality and morbidity, mainly in surgical ICU patients, remains to be proven. Also, citrate administration in the predilution mode appears to be safe and exempt of relevant side effects, yet still requires rigorous monitoring. Current consensus exists about using a CRRT dose of 25 ml/kg/h in non-septic AKI. However, because patients should not be undertreated, this implies that doses as high as 30 to 35 ml/kg/h must be prescribed to account for eventual treatment interruptions. Awaiting results from large, ongoing trials, 35 ml/kg/h should remain the standard dose in septic AKI, particularly when shock is present. To date, exact timing of CRRT is not well defined. A widely accepted composite definition of timing is needed before an appropriate study challenging this major issue can be launched.


Intensive blood pressure lowering increases cerebral blood flow in older subjects with hypertension.
Hypertension is associated with reduced cerebral blood flow (CBF). Intensive (<130/80 mm Hg) blood pressure (BP) lowering in older people might give greater reduction in cardiovascular risk, but there are concerns that this might produce hypoperfusion which may precipitate falls and possibly stroke. We determined the effect of intensive compared with usual BP lowering on CBF in hypertensive older subjects. Individuals aged >70 years with a history of systolic hypertension on 1 or no BP lowering drugs were recruited from primary care (n=37; age, 75±4 years; systolic BP, >150 mm Hg) and randomized to receive intensive (target BP, <130/80 mm Hg) or usual (target BP, <140/85 mm Hg) BP lowering for 12 weeks, with reviews every 2 weeks. CBF, determined using 3T arterial spin labeling MRI, and 24-hour ambulatory BP were performed at baseline and after 12 weeks of treatment. Baseline BP (ambulatory or in clinic) and baseline gray matter CBF were not significantly different between the groups. After treatment, BP was reduced significantly in both groups but fell more in the intensive group (26/17 versus 15/5 mm Hg; P<0.01). Over the same period, gray matter CBF increased significantly in the intensive group (7±11 mL/min per 100 g; P=0.013) but was unchanged in the usual BP target group (-3±9 mL/min per 100 g; P=0.23); P<0.01 for comparison. Intensive BP lowering in older people with hypertension increases CBF, compared with BP lowering to usual target. These findings suggest hypertension in older people shifts the autoregulatory CBF curve rightward and downward and is reversible with BP lowering.


Anoxic Brain Injury Detection with the Normalized Diffusion to ASL Perfusion Ratio: Implications for Blood-Brain Barrier Injury and Permeability.
Anoxic brain injury is a result of prolonged hypoxia. We sought to describe the nonquantitative arterial spin-labeling perfusion imaging patterns of anoxic brain injury, characterize the relationship of arterial spin-labeling and DWI, and evaluate the normalized diffusion-to-perfusion ratio to differentiate patients with anoxic brain injury from healthy controls. We identified all patients diagnosed with anoxic brain injuries from 2002 to 2019. Twelve ROIs were drawn on arterial spin-labeling with coordinate-matched ROIs identified on DWI. Linear regression analysis was performed to examine the relationship between arterial spin-labeling perfusion and diffusion signal. Normalized diffusion-to-perfusion maps were generated using a custom-built algorithm. Thirty-five patients with anoxic brain injuries and 34 healthy controls were identified. Linear regression analysis demonstrated a significant positive correlation between arterial spin-labeling and DWI signal. By means of a combinatory cutoff of slope of >0 and R2 of > 0.78, linear regression using arterial spin-labeling and DWI showed a sensitivity of 0.86 (95% CI, 0.71-0.94) and specificity of 0.82 (95% CI, 0.66-0.92) for anoxic brain injuries. A normalized diffusion-to-perfusion color map demonstrated heterogeneous ratios throughout the brain in healthy controls and homogeneous ratios in patients with anoxic brain injuries. In anoxic brain injuries, a homogeneously positive correlation between qualitative perfusion and DWI signal was identified so that areas of increased diffusion signal showed increased ASL signal. By exploiting this relationship, the normalized diffusion-to-perfusion ratio color map may be a valuable imaging biomarker for diagnosing anoxic brain injury and potentially assessing BBB integrity.