Neurologic soft signs and low birthweight: their association and neuropsychiatric implications.
We examine the relationship between neurologic soft signs and cognitive deficits, learning disorders, and psychiatric problems in low birthweight (LBW) and normal birthweight (NBW) children. Representative samples of LBW and NBW children were selected from the 1983-1985 newborn discharges of two major hospitals in Michigan. Eight hundred-twenty three children (75% of the target sample) were evaluated at ages 6 and 11. A standardized neurologic evaluation was used by neurologists to measure neurologic soft signs at age 6 (children with frank neurologic impairment were excluded). IQ was measured by WISC-R and behavior problem lists were rated by mothers and teachers. Standard tests of academic achievement were used to identify learning disorders. All assessments were blind to LBW status. Using multiple regression analysis, applying generalized estimating equations (GEE), we estimated the effects of soft signs on 3 behavioral domains, based on information from multiple informants and times of assessment. LBW was associated with a two-fold increased risk for soft signs. Soft signs increased the risk for subnormal IQ and for learning disorders in children with normal IQ. Soft signs were associated with excess internalizing problems in LBW and NBW children, and with attention and externalizing problems in LBW children; the excess in externalizing problems in LBW children was observed only at age 6. Soft signs are a marker of high risk for cognitive and psychiatric problems. Of particular concern is their presence in LBW children, in whom they are associated with more severe cognitive deficits and more pervasive psychiatric problems.


Perioperative safety of two-team simultaneous bilateral total knee arthroplasty in the obese patient.
Although the rates of perioperative morbidity and mortality with simultaneous bilateral total knee arthroplasty remain a concern, multiple studies have shown the procedure to be safe in selected patient populations. Evidence also remains mixed regarding the outcomes of total knee arthroplasty in obese patients. The purpose of this paper is to compare the rates of perioperative morbidity and mortality in consecutive obese patients undergoing two-team simultaneous bilateral total knee arthroplasty and unilateral total knee arthroplasty. The records on all two-team simultaneous total knee arthroplasties and unilateral total knee arthroplasties from October 1997 to December 2007 were reviewed. A total of 151 patients with a body mass index (BMI) >30 undergoing two-team simultaneous total knee arthroplasty and 148 patients with a BMI >30 undergoing unilateral total knee arthroplasty were retrospectively reviewed and analyzed to determine perioperative morbidity and mortality as well as one-year mortality rates. Preoperative patient characteristics did not show any significant differences between groups. The simultaneous bilateral group had significantly longer operative times (127.4 versus 112.7 minutes, p < 0.01), estimated blood loss (176.7 versus 111.6 mL, p = 0.01), percentage of patients requiring blood transfusion (64.9% versus 13.9%, p < 0.01), length of hospital stay (3.72 versus 3.30 days, p < 0.01), and percentage of patients requiring extended care facility usage at discharge (63.6% versus 27.8%, p < 0.01). No significant difference between unilateral and bilateral groups was seen in regards to total complication rate, major or minor complication subgroup rate, or any particular complication noted. Doubling the variables in the unilateral group for a staged total knee arthroplasty scenario did create significant increases over the simultaneous data in almost every data category. Two-team simultaneous total knee arthroplasty appears to be safe in obese patients, with similar complication rates as compared to unilateral procedures. Two-team simultaneous total knee arthroplasty also appears to have potential benefits over a staged procedure in the obese patient, although more study is required regarding this topic.


Olivine and pyroxene diversity in the crust of Mars.
Data from the Observatoire pour la Minéralogie, l'Eau, les Glaces, et l'Activité (OMEGA) on the Mars Express spacecraft identify the distinct mafic, rock-forming minerals olivine, low-calcium pyroxene (LCP), and high-calcium pyroxene (HCP) on the surface of Mars. Olivine- and HCP-rich regions are found in deposits that span the age range of geologic units. However, LCP-rich regions are found only in the ancient Noachian-aged units, which suggests that melts for these deposits were derived from a mantle depleted in aluminum and calcium. Extended dark regions in the northern plains exhibit no evidence of strong mafic absorptions or absorptions due to hydrated materials.


Magnetic domain wall conduits for single cell applications.
The ability to trap, manipulate and release single cells on a surface is important both for fundamental studies of cellular processes and for the development of novel lab-on-chip miniaturized tools for biological and medical applications. In this paper we demonstrate how magnetic domain walls generated in micro- and nano-structures fabricated on a chip surface can be used to handle single yeast cells labeled with magnetic beads. In detail, first we show that the proposed approach maintains the microorganism viable, as proven by monitoring the division of labeled yeast cells trapped by domain walls over 16 hours. Moreover, we demonstrate the controlled transport and release of individual yeast cells via displacement and annihilation of individual domain walls in micro- and nano-sized magnetic structures. These results pave the way to the implementation of magnetic devices based on domain walls technology in lab-on-chip systems devoted to accurate individual cell trapping and manipulation.


A systematic review on the relationship between mental health, radicalization and mass violence.
Radicalization is a process, by which individuals adopt extreme political, social and religious ideation that leads to mass violence acts. It has been hypothesized that mental health characteristics might be associated with a risk of radicalization. However, a qualitative synthesis of studies investigating the relationship between mental health and radicalization has not been performed so far. Therefore, we aimed to perform a systematic review of studies examining the association between mental health characteristics and the risk of radicalization. Two reviewers performed an independent search of online databases from their inception until 8th April 2018 and 12 publications met eligibility criteria. There were several methodological limitations across the majority of eligible publications, including doubtful sample representativeness, use of diagnostic procedures without personal assessment of mental health status or lack of standardized tools for assessment of mental health. Representative cross-sectional studies revealed that depressive symptoms might be associated with radicalization proneness. However, it remains unknown whether depressive symptoms are associated with resilience or vulnerability to radicalization. Another finding from our systematic review is that several personality traits might predispose to develop extreme ideation. Finally, there is some evidence that lone-actors might represent a specific subgroup of subjects with extreme beliefs which can be characterized by high prevalence of psychotic and/or mood disorders. In conclusion, this systematic review indicates that caution should be taken on how the association between 'mental health' and 'radicalization' is being claimed, because of limited evidence so far, and a number of methodological limitations of studies addressing this issue.


Active stabilization of a rapidly chirped laser by an optoelectronic digital servo-loop control.
We propose and demonstrate a novel active stabilization scheme for wide and fast frequency chirps. The system measures the laser instantaneous frequency deviation from a perfectly linear chirp, thanks to a digital phase detection process, and provides an error signal that is used to servo-loop control the chirped laser. This way, the frequency errors affecting a laser scan over 10 GHz on the millisecond timescale are drastically reduced below 100 kHz. This active optoelectronic digital servo-loop control opens new and interesting perspectives in fields where rapidly chirped lasers are crucial.


Reducing Disaster Exacerbated Non-Communicable Diseases Through Public Health Infrastructure Resilience: Perspectives of Australian Disaster Service Providers.
The exposure of people and infrastructure to flood and storm related disasters across the world is increasing faster than vulnerability is decreasing. For people with non-communicable diseases this presents a significant risk as traditionally the focus of disaster management systems has been on immediate trauma and communicable diseases. This focus must now be expanded to include the management of non-communicable diseases because these conditions are generating the bulk of ill health, disability and premature death around the globe. When public health service infrastructure is destroyed or damaged access to treatment and care is severely jeopardised, resulting in an increased risk of non-communicable disease exacerbation or even death. This research proposes disaster responders, coordinators and government officials are vital assets to mitigate and eventually prevent these problems from being exacerbated during a disaster. This is due to their role in supporting the public health service infrastructure required to maximise treatment and care for people with non-communicable diseases. By focusing on the disaster cycle as a template, and on mitigation and prevention phases in particular, these actions and activities performed by disaster service responders will lead to overall improved preparedness, response, recovery and rehabilitation phases. Data were collected via 32 interviews and one focus group (eight participants) between March 2014 and August 2015 (total of 40 participants). The research was conducted in the State of Queensland, Australia, with disaster service providers. The analysis included the phases of: organizing data; data description; data classification; and interpretation. The research found a relationship between the impact of a disaster on public health service infrastructure, and increased health risks for people with non-communicable diseases. Mitigation strategies were described for all phases of the disaster cycle impacting public health service infrastructure. Specific measures include: increasing the use of telemedicine; preplanning with medical suppliers; effective town planning; health professionals visiting evacuation centers; evacuation centers having power for medical equipment; hubs for treatment and care after a disaster; evacuation of high risk people prior to disaster; mapping people at risk by non-communicable disease; and a mechanism for sharing information between agencies. A common theme from the participants was that having accurate and easily accessible data on people with non-communicable diseases would allow disaster service providers to adequately prepare for and respond to a disaster. Disaster service providers can play a vital role in reducing the risk of disaster exacerbated non-communicable diseases through public health service infrastructure resilience. They are often employed in communities where disasters occur and are therefore best-placed to lead implementation of the mitigation strategies identified in this research. To sustainably implement the mitigation strategies they will need to become integrated into effective performance and monitoring of the disaster response and health sector during non-disaster periods. For this to occur, the strategies should be integrated into business and strategic plans. Achieving this will help implement the Sendia Framework for Disaster Risk Reduction 2015-2030 and, most importantly, help protect the health of people with non-communicable diseases before, during and after a disaster.


Chemistry of personalized solar energy.
Personalized energy (PE) is a transformative idea that provides a new modality for the planet's energy future. By providing solar energy to the individual, an energy supply becomes secure and available to people of both legacy and nonlegacy worlds and minimally contributes to an increase in the anthropogenic level of carbon dioxide. Because PE will be possible only if solar energy is available 24 h a day, 7 days a week, the key enabler for solar PE is an inexpensive storage mechanism. HY (Y = halide or OH(-)) splitting is a fuel-forming reaction of sufficient energy density for large-scale solar storage, but the reaction relies on chemical transformations that are not understood at the most basic science level. Critical among these are multielectron transfers that are proton-coupled and involve the activation of bonds in energy-poor substrates. The chemistry of these three italicized areas is developed, and from this platform, discovery paths leading to new hydrohalic acid- and water-splitting catalysts are delineated. The latter water-splitting catalyst captures many of the functional elements of photosynthesis. In doing so, a highly manufacturable and inexpensive method for solar PE storage has been discovered.


Variation in risk and mortality of acute kidney injury in critically ill patients: a multicenter study.
Despite standardized definitions of acute kidney injury (AKI), there is wide variation in the reported rates of AKI and hospital mortality for patients with AKI. Variation could be due to actual differences in disease incidence, clinical course, or a function of data ascertainment and application of diagnostic criteria. Using standard criteria may help determine and compare the risk and outcomes of AKI across centers. In this cohort study of critically ill patients admitted to the intensive care units at six hospitals in four countries, we used KDIGO criteria to define AKI. The main outcomes were the occurrence of AKI and hospital mortality. Of the 15,132 critically ill patients, 32% developed AKI based on serum creatinine criteria. After adjusting for differences in age, sex, and severity of illness, the odds ratio for AKI continued to vary across centers (odds ratio (OR), 2.57-6.04, p < 0.001). The overall, crude hospital mortality of patients with AKI was 27%, which also varied across centers after adjusting for KDIGO stage, differences in age, sex, and severity of illness (OR, 1.13-2.20, p < 0.001). The severity of AKI was associated with incremental mortality risk across centers. In this study, the absolute and severity-adjusted rates of AKI and hospital mortality rates for AKI varied across centers. Future studies should examine whether variation in the risk of AKI among centers is due to differences in clinical practice or process of care or residual confounding due to unmeasured factors.


The role of stromal cancer-associated fibroblasts in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6. The role of downstream signaling pathways including JAK/STAT, mTOR, sonic hedge hog (SHH), and NFkB have also been shown to play an important function in PDAC-CAF cross talk. The role of autophagy and other metabolic effects on each cell type within the tumor have also been proposed to play roles in facilitating CAF secretory function and enhancing tumor growth in a low-glucose microenvironment. Targeting the stroma has gained interest with multiple preclinical and clinical trials targeting SHH, JAK2, and methods of either exploiting the secretory capability of CAFs to enhance drug delivery or inhibiting it to prevent its influence on cancer cell chemoresistance. This review summarizes the most recent progress made in understanding stromal formation; its contribution to tumor proliferation, invasion, and metastasis; its role in chemoresistance; and potential therapeutic strategies on the horizon.


Distribution of N-methyl-D-aspartate-sensitive L-[3H]glutamate-binding sites in rat brain.
N-methyl-D-aspartate (NMDA) is an acidic amino acid which depolarizes neurons by selectively interacting with a distinct class of excitatory amino acid receptor. Recent evidence has indicated that this receptor is a neurotransmitter receptor in the spinal cord, cerebral cortex, and hippocampus for which the endogenous ligand is likely to be L-glutamate or a structurally related compound. Using quantitative autoradiography, we have studied the anatomical distribution of the class of L-[3H]glutamate-binding sites displaced by NMDA, which appear to correspond to NMDA receptors. The CA1 region of the hippocampus contains the highest density of sites. In general, telencephalic regions have high levels of binding sites. The cerebral cortex shows significant density variations among the differing layers and regions, with the highest levels found in the frontal cortex layers I to III. Within the basal ganglia, the highest levels are found in the nucleus accumbens, intermediate levels are found in the caudate/putamen, and very low levels are found in the globus pallidus. Thalamic regions have moderate levels with variations among differing regions. Midbrain and brainstem have low levels of binding sites, but within these regions there are structures exhibiting higher levels, e.g., the nucleus of the solitary tract and the inferior olive. The distribution of NMDA sites is consistent with most, but not all, of the regions previously proposed to use glutamate as an excitatory transmitter. Thus, the distribution of NMDA-sensitive L-[3H]glutamate-binding sites suggests that the NMDA receptor represents a major, distinct subset of excitatory amino acid receptors and indicates regions in which neurotransmission may be mediated or modulated by this receptor.


Exposing immature hippocampal neurons to excitotoxins reveals distinct transcriptome and protein regulation with induction of common survival signaling pathways.
Early life traumas lead to neuroprotection by preconditioning mechanisms. To determine which genes and pathways are most likely involved in specific adaptive effects, immature hippocampal cultures were exposed to a single high dose of glutamate (250 μM), NMDA (100 μM), or KA (300 μM) for 48 h (5-7 DIV) based on our prior "two hit" in vitro model of preconditioning. Transcriptome profiling and immunocytochemistry of gene candidates were performed 7 days later when cultured neurons mature (14 DIV). Many genes were up- and down- regulated involving distinct Ca2+-binding protein families, G-coupled proteins, various growth factors, synaptic vesicle docking factors, certain neurotransmitter receptors, heat shock, oxidative stress, and certain anti-apoptotic Bcl-2 gene members that influence neuronal survival. Immunohistochemistry showed a marked decrease in the number of Calb1 and Calm2 positive neurons following NMDA but not after glutamate exposure whereas ryanodine and Cav1.2 voltage gated channel expression was less affected. Survivors had marked increases in Calm2 immunostaining; however, high-density neural clusters observed in controls, were depleted after NMDA and partly diminished after glutamate. While NR1 mRNA expression was decreased in the microarray, specific antibodies revealed selective loss of the NR1C1 splice variant. Calm2 which can inactivate NMDA receptors by binding to C1 but not C2 regions of its NR1 subunit suggests that loss of the C1 splice variant will reduce co-regulation with Calm2 and alter NR1 trafficking, phosphorylation, and NMDA currents following early life NMDA exposure. A dramatic reduction in the density of GABAAα5 and GABAB receptor expressing neurons was observed after NMDA exposure but immunodensity measurements were unchanged as was the expression of the GABA synthesizing enzyme, GAD, suggesting that fast inhibitory neurotransmission and response to benzodiazepines and GABAB-mediated IPSPs may be preserved in matured survivors. Selective upregulation of Chat and CNRIP was detected after glutamate treatment suggesting this condition would decrease cholinergic and excitatory neurotransmission by decreasing Ach content and CB1 interacting protein function. This decrease likely contributes to memory and attention tasks deficits that follow a single early neurological insult. Diverse changes that follow overactivation of excitatory networks of immature neurons appear long-lasting or permanent and are expected to have profound effects on network function and adaptive responses to further insult.


New self-reporting questionnaire to assess urinary tract infections and differential diagnosis: acute cystitis symptom score.
Development and validation of a simple and standardized self-reporting questionnaire for acute uncomplicated cystitis (AUC) assessing typical and differential symptoms, quality of life and possible changes after therapy in female patients with AUC. Literature research, development and evaluation of the Acute Cystitis Symptom Score (ACSS), an 18-item self-reporting questionnaire including (a) six questions about 'typical' symptoms of AUC, (b) four questions regarding differential diagnoses, (c) three questions on quality of life and (d) five questions on additional conditions which may affect therapy. The ACSS was evaluated in 286 women (mean age 32.3 ± 12.3 years) in the Russian and Uzbek language. Measurements of reliability, validity, predictive ability and responsiveness were performed. Cronbach's alpha for the ACSS was 0.89, split-half reliability was 0.92 and correlation between halves was 0.85. Mann-Whitney test revealed significant difference scores of the 'typical' domain between patients and controls (10.75 vs. 2.02, p < 0.001). The optimal threshold score was 6 points, with a 94% sensitivity and 90% specificity to predict AUC. The symptom score decreased significantly when comparing before and after therapy (10.7 vs. 2.1, p < 0.001). The new validated ACSS is accurate enough and can be recommended for clinical studies and practice for initial diagnosis and monitoring treatment of AUC. Evaluation in other languages is in progress.


Low dose oral haloperidol does not prolong QTc interval in older acutely hospitalised adults: a subanalysis of a randomised double-blind placebo-controlled study.
Haloperidol is the most frequently prescribed antipsychotic for delirium symptoms. The risk of QTc prolongation often raises concerns, although the effect of haloperidol on QTc interval has not yet been investigated in a randomised placebo-controlled fixed-dose study. A subanalysis of a randomised double-blind placebo-controlled study was conducted to evaluate the effect of prophylactic haloperidol 1 mg or placebo 1 mg orally twice-daily (maximum of 14 doses) on QTc interval in patients aged 70 years and over. Bedside, 12-lead ECGs were recorded before, during and after the one-week intervention period. Automatic QTc measurements were obtained in addition to manual measurements of QT and RR intervals, blinded for treatment status. Manual measurements were corrected (QTc) using Bazett (QTc-B), Framingham (QTc-Fa), Fridericia (QTc-Fi) and Hodges (QTc-H) methods. Mixed model analyses were used to test for differences in longitudinal course of QTc between patients receiving haloperidol and placebo. ECG recordings of 72 patients (haloperidol n = 38) were analysed, 45.8% male. Median (range) haloperidol serum concentration on day 4 was 0.71 (0.32-1.82) µg/L (n = 23). Longitudinal course of mean QTc did not significantly differ between treatment arms for any of the automatic or manually derived QTc values. Low dose oral haloperidol did not result in QTc prolongation in older acutely hospitalised patients. Results may not be generalizable to patients with existing ECG abnormalities such as atrial fibrillation.


Influence of amphetamines on plasma corticosteroid and growth hormone levels in man.
Plasma fluorogenic corticosteroid and immunoreactive growth hormone levels rose significantly after the intravenous administration of methylamphetamine to healthy young men at various times of the day. The rise in corticosteroids was most pronounced in the evening and was accompanied by an increase in circulating levels of immunoreactive corticotrophin. Oral dexamphetamine also resulted in significant rises in plasma corticosteroids but not in growth hormone. These hormonal changes were accompanied by evidence of mild central stimulation. Though they may be part of an associated and non-specific response, it is more likely that they represent specific effects of amphetamines on centres in the hypothalamus or midbrain controlling secretion of corticotrophin and growth hormone releasing factors.


Validity of the posterior tibial edema sign in posterior tibial tendon dysfunction.
Posterior tibial tendon dysfunction (PTTD) is a common malady leading to acquired flatfoot, which frequently causes foot and ankle pain and swelling. We hypothesized that patients with PTTD and pitting edema along the course of the posterior tibial tendon (PTT) would have evidence of fluid within the tendon sheath on MRI. We introduce and validate a novel, yet simple physical examination finding, the posterior tibial edema (PTE) sign, to help distinguish PTTD from other causes of foot and ankle pain and swelling. To determine an association between the PTE sign and changes to the PTT evident on MRI, we reviewed the medical records of patients with PTTD who underwent magnetic resonance imaging (MRI). Of 186 patients identified with PTTD, 49 underwent MRI, and 42 (86%) demonstrated imaging characteristics consistent with tendonitis, tendinosis, or tenosynovitis. Presence or absence of increased posterior malleolar pitting edema agreed with presence or absence of these MRI findings in 43 patients (88%), making the clinical examination finding significantly predictive of MRI results (p= 0.01). The sensitivity of the test for PTE was 86%, with specificity of 100%. The PTE sign refers to pitting edema along the course of the PTT, not associated with acute trauma and not accompanied by other areas of edema. Physical examination signs that are highly sensitive and specific to the condition may help lower the cost of diagnosis by eliminating the need for expensive tests that are not always necessary.


Transgenic parasites stably expressing full-length Plasmodium falciparum circumsporozoite protein as a model for vaccine down-selection in mice using sterile protection as an endpoint.
Circumsporozoite protein (CSP) of Plasmodium falciparum is a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenic Plasmodium berghei malaria parasite stably expressing a functional full-length P. falciparum CSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.


The effect of variations in nurse staffing on patient length of stay in the acute care setting.
This study examines the relationship between nurse staffing and patient length of stay (LOS). Data were collected on nurses employed and patients admitted to one of four study units located in two Midwest hospitals. Three nursing variables (hours per patient day [HPPD], skill mix, and nursing expertise) were collected through survey and administrative forms. The nursing data were then linked with patient-specific characteristics (deviation from expected LOS) to test the relationship at the patient level of analysis. Average HPPD was a positive predictor of deviation from expected LOS, whereas overall expertise was a negative predictor of deviation from expected LOS. Higher staffing levels may result in patients being discharged sooner than expected. Nurse administrators must consider the quantity as well as quality of staff when determining optimal staffing levels. Unit staffing levels must include nurses who have both experiential and theoretical knowledge in order to achieve optimal patient outcomes.


Multi-voxel patterns of visual category representation during episodic encoding are predictive of subsequent memory.
Successful encoding of episodic memories is thought to depend on contributions from prefrontal and temporal lobe structures. Neural processes that contribute to successful encoding have been extensively explored through univariate analyses of neuroimaging data that compare mean activity levels elicited during the encoding of events that are subsequently remembered vs. those subsequently forgotten. Here, we applied pattern classification to fMRI data to assess the degree to which distributed patterns of activity within prefrontal and temporal lobe structures elicited during the encoding of word-image pairs were diagnostic of the visual category (Face or Scene) of the encoded image. We then assessed whether representation of category information was predictive of subsequent memory. Classification analyses indicated that temporal lobe structures contained information robustly diagnostic of visual category. Information in prefrontal cortex was less diagnostic of visual category, but was nonetheless associated with highly reliable classifier-based evidence for category representation. Critically, trials associated with greater classifier-based estimates of category representation in temporal and prefrontal regions were associated with a higher probability of subsequent remembering. Finally, consideration of trial-by-trial variance in classifier-based measures of category representation revealed positive correlations between prefrontal and temporal lobe representations, with the strength of these correlations varying as a function of the category of image being encoded. Together, these results indicate that multi-voxel representations of encoded information can provide unique insights into how visual experiences are transformed into episodic memories.


Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.
Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.


A high methionine, low folate and vitamin B6/B12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1.
Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B6 (0.01 mg/kg), and B12 (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4th week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B6/B12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018.


Tenascin expression in astrocytomas correlates with angiogenesis.
We investigated the expression and distribution of the extracellular matrix protein tenascin (TN) in 59 astrocytomas and 11 samples of normal brain by Western blot analysis and immunohistochemistry using antibodies against human TN. The tumors included 14 juvenile pilocytic astrocytomas (grade 1), 13 low grade fibrillary astrocytomas (grade II), 8 anaplastic astrocytomas (grade III), and 24 glioblastomas multiforme (grade IV). Proliferation indices were calculated by computer-based image analysis after immunostaining with the MIB-1 antibody against the Ki-67 proliferation-associated antigen. Western blot analysis for TN on fresh frozen tumor tissue from 23 of the 59 astrocytomas indicated up to 4-fold higher TN expression in glioblastomas multiforme than in nontumorous control tissues. Enhanced intercellular expression of TN was observed by immunohistochemistry in glioblastomas multiforme. More-over, TN immunostaining was consistently greater within and around the walls of hyperplastic blood vessels than nonhyperplastic vessels of both high grade tumors and juvenile pilocytic astrocytomas. Juvenile pilocytic astrocytomas with increased TN expression by Western blot analysis had vascular hyperplasia by light microscopy. Proliferation indices moderately correlated with tumor grade. Enhanced immunohistochemical expression of TN was associated with higher tumor grade with higher proliferation indices. The strong association of TN and vascular hyperplasia, regardless of tumor grade, suggests that TN may play a crucial role in angiogenesis.


[New genetic tests and their clinical utility for cancer screening].
The promises resulting from the decoding of the human genome have not been fulfilled to the extent as expected. At the same time it is fair to say that the results of recent genetic research have not been useless. In the area of familial cancer the clinical benefit of genetic testing for healthy family members is very convincing, where the risk of disease can be reduced substantially through preventive interventions. For example, prophylactic mastectomy and premenopausal ovariectomy can reduce the cancer risk in carriers of BRCA1 and BRCA2 mutations dramatically. In recent years, the research has moved towards the decoding of the genetic causes of sporadic cancers as well. Genome-wide and hypothesis-free association studies have linked different chromosome regions to cancer. By this, new insights into disease mechanisms could be gained, an important requirement for the development of diagnostics and drugs. However, what is missing is the evidence that the associated SNPs (Single Nucleotide Polymorphisms) could be useful for individual risk calculation or for stratification of the population into groups with different preventive or screening needs.


Using NS5B Sequencing for Hepatitis C Virus Genotyping Reveals Discordances with Commercial Platforms.
We aimed to evaluate the correct assignment of HCV genotypes by three commercial methods-Trugene HCV genotyping kit (Siemens), VERSANT HCV Genotype 2.0 assay (Siemens), and Real-Time HCV genotype II (Abbott)-compared to NS5B sequencing. We studied 327 clinical samples that carried representative HCV genotypes of the most frequent geno/subtypes in Spain. After commercial genotyping, the sequencing of a 367 bp fragment in the NS5B gene was used to assign genotypes. Major discrepancies were defined, e.g. differences in the assigned genotype by one of the three methods and NS5B sequencing, including misclassification of subtypes 1a and 1b. Minor discrepancies were considered when differences at subtype levels, other than 1a and 1b, were observed. The overall discordance with the reference method was 34% for Trugene and 15% for VERSANT HCV2.0. The Abbott assay correctly identified all 1a and 1b subtypes, but did not subtype all the 2, 3, 4 and 5 (34%) genotypes. Major discordances were found in 16% of cases for Trugene HCV, and the majority were 1b- to 1a-related discordances; major discordances were found for VERSANT HCV 2.0 in 6% of cases, which were all but one 1b to 1a cases. These results indicated that the Trugene assay especially, and to a lesser extent, Versant HCV 2.0, can fail to differentiate HCV subtypes 1a and 1b, and lead to critical errors in clinical practice for correctly using directly acting antiviral agents.


Effect of donor age on the proportion of mesenchymal stem cells derived from anterior cruciate ligaments.
The characteristics of anterior cruciate ligament (ACL)-derived mesenchymal stem cells (MSCs), such as proportion and multilineage potential, can be affected by donor age. However, the qualitative and quantitative features of ACL MSCs isolated from younger and older individuals have not yet been compared directly. This study assessed the phenotypic and functional differences in ACL-MSCs isolated from younger and older donors and evaluated the correlation between ACL-MSC proportion and donor age. Torn ACL remnants were harvested from 36 patients undergoing ACL reconstruction (young: 29.67 ± 10.92 years) and 33 undergoing TKA (old: 67.96 ± 5.22 years) and the proportion of their MSCs were measured. The mean proportion of MSCs was slightly higher in older ACL samples of the TKA group than of the younger ACL reconstruction group (19.69 ± 8.57% vs. 15.33 ± 7.49%, p = 0.024), but the proportions of MSCs at passages 1 and 2 were similar. MSCs from both groups possessed comparable multilineage potentiality, as they could be differentiated into adipocytes, osteocytes, and chondrocytes at similar level. No significant correlations were observed between patient age and MSC proportions at passages 0-2 or between age and MSC proportion in both the ACL reconstruction and TKA groups. Multiple linear regression analysis found no significant predictor of MSC proportion including donor age for each passage. Microarray analysis identified several genes that were differentially regulated in ACL-MSCs from old TKA patients compared to young ACL reconstruction patients. Genes of interest encode components of the extracellular matrix (ECM) and may thus play a crucial role in modulating tissue homeostasis, remodeling, and repair in response to damage or disease. In conclusion, the proportion of freshly isolated ACL-MSC was higher in elderly TKA patients than in younger patients with ACL tears, but their phenotypic and multilineage potential were comparable.


Constructing Statistically Unbiased Cortical Surface Templates Using Feature-Space Covariance.
The choice of surface template plays an important role in cross-sectional subject analyses involving cortical brain surfaces because there is a tendency toward registration bias given variations in inter-individual and inter-group sulcal and gyral patterns. In order to account for the bias and spatial smoothing, we propose a feature-based unbiased average template surface. In contrast to prior approaches, we factor in the sample population covariance and assign weights based on feature information to minimize the influence of covariance in the sampled population. The mean surface is computed by applying the weights obtained from an inverse covariance matrix, which guarantees that multiple representations from similar groups (e.g., involving imaging, demographic, diagnosis information) are down-weighted to yield an unbiased mean in feature space. Results are validated by applying this approach in two different applications. For evaluation, the proposed unbiased weighted surface mean is compared with un-weighted means both qualitatively and quantitatively (mean squared error and absolute relative distance of both the means with baseline). In first application, we validated the stability of the proposed optimal mean on a scan-rescan reproducibility dataset by incrementally adding duplicate subjects. In the second application, we used clinical research data to evaluate the difference between the weighted and unweighted mean when different number of subjects were included in control versus schizophrenia groups. In both cases, the proposed method achieved greater stability that indicated reduced impacts of sampling bias. The weighted mean is built based on covariance information in feature space as opposed to spatial location, thus making this a generic approach to be applicable to any feature of interest.


A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism.
Erythropoietin (Epo) is neuroprotective in a number of preparations, but can lead to unacceptably high and even lethal hematocrit levels. Recent reports show that modified Epo variants confer neuroprotection in models of glaucoma and retinal degeneration without raising hematocrit. In this study, neuroprotective effects of two Epo variants (EpoR76E and EpoS71E) were assessed in a model of Parkinson's disease. The constructs were packaged in recombinant adeno-associated viral (rAAV) vectors and injected intramuscularly. After 3 weeks, mice received five daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were killed 5 weeks later. The MPTP-lesioned mice pretreated with rAAV.eGFP (negative control) exhibited a 7- to 9-Hz tremor and slower latencies to move on a grid test (akinesia). Both of these symptomatic features were absent in mice pretreated with either modified Epo construct. The rAAV.eGFP-treated mice lesioned with MPTP exhibited a 41% reduction in tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rAAV.EpoS71E construct did not protect nigral neurons, but neuronal loss in mice pretreated with rAAV.EpoR76E was only half that of rAAV.eGFP controls. Although dopamine levels were normal in all groups, 3,4-dihydroxyphenylacetic acid (DOPAC) was significantly reduced only in MPTP-lesioned mice pretreated with rAAV.eGFP, indicating reduced dopamine turnover. Analysis of TH-positive fibers in the striatum showed normalized density in MPTP-lesioned mice pretreated with rAAV.EpoS71E, suggesting that enhanced sprouting induced by EpoS71E may have been responsible for normal behavior and dopaminergic tone in these mice. These results show that systemically administered rAAV-generated non-erythropoietic Epo may protect against MPTP-induced parkinsonism by a combination of neuroprotection and enhanced axonal sprouting.


Reasons for migration among medical students from Karachi.
The subject of economic migration among health care professionals has received intense attention. However, the aetiology of this migration has not been rigorously evaluated in Pakistan. Such knowledge can potentially influence health care and academic policies. Our current study proposes to quantify the relative contributions of various personal, professional and economic variables among final-year medical students in Karachi. A self-administered structured questionnaire using a 10-point scale was developed and piloted among Karachi medical students. Additional open-ended questions were included to allow us to capture information not otherwise covered in the questionnaire. SPSS software was used for data entry and analysis. Over 95% of Aga Khan University (AKU) and over 65% of Baqai University (BU) final-year medical students intend to proceed abroad for their postgraduate training. The 2 most important factors behind this intent as pointed out by the students are poor salary structure (AKU mean score 8.94 +/- 1.73, BU mean score 7.14 +/- 2.6) and poor quality of training in the home country (AKU mean score 9.20 +/- 1.20, BU mean score 8.68 +/- 2.03). Other interesting factors captured through the open-ended questions were the poor work environment and lack of rigor in teaching of residents in domestic university hospitals. Over 50% of final-year medical students cited these issues as major reasons behind their decision to migrate.


Critical Value Reporting in Transfusion Medicine: A Survey of Communication Practices in US Facilities.
While critical value procedures have been adopted in most areas of the clinical laboratory, their use in transfusion medicine has not been reviewed in detail. The results of this study present a comprehensive overview of critical value reporting and communication practices in transfusion medicine in the United States. A web-based survey was developed to collect data on the prevalence of critical value procedures and practices of communicating results. The survey was distributed via email to US hospital-based blood banks. Of 123 facilities surveyed, 84 (68.3%) blood banks had a critical value procedure. From a panel of 23 common blood bank results, nine results were selected by more than 70% of facilities as either a critical value or requiring rapid communication as defined by an alternate procedure. There was overlap among results communicated by facilities with and without a critical value procedure. The most frequently communicated results, such as incompatible crossmatch for RBC units issued uncrossmatched, delay in finding compatible blood due to a clinically significant antibody, and transfusion reaction evaluation suggestive of a serious adverse event, addressed scenarios associated with the leading reported causes of transfusion-related fatalities.


Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): a single-blind, multicentre, randomised controlled trial.
Systemic sepsis is a major cause of death in preterm neonates. There are compelling theoretical reasons why treatment with haemopoietic colony-stimulating factors might reduce sepsis and improve outcomes, and as a consequence these agents have entered into use in neonatal medicine without adequate evidence. We assessed whether granulocyte-macrophage colony stimulating factor (GM-CSF) administered as prophylaxis to preterm neonates at high risk of neutropenia would reduce sepsis, mortality, and morbidity. We undertook a single-blind, multicentre, randomised controlled trial in 26 centres between June, 2000, and June, 2006. 280 neonates of below or equal to 31 weeks' gestation and below the 10th centile for birthweight were randomised within 72 h of birth to receive GM-CSF 10 microg/kg per day subcutaneously for 5 days or standard management. From recruitment to day 28 a detailed daily clinical record form was completed by the treating clinicians. Primary outcome was sepsis-free survival to 14 days from trial entry. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN42553489. Neutrophil counts after trial entry rose significantly more rapidly in infants treated with GM-CSF than in control infants during the first 11 days (difference between neutrophil count slopes 0.34 x 10(9)/L/day; 95% CI 0.12-0.56). There was no significant difference in sepsis-free survival for all infants (93 of 139 treated infants, 105 of 141 control infants; difference -8%, 95% CI -18 to 3). A meta-analysis of this trial and previous published prophylactic trials showed no survival benefit. Early postnatal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely preterm neonates.


Cost-effectiveness of using a social franchise network to increase uptake of oral rehydration salts and zinc for childhood diarrhea in rural Myanmar.
This paper examines the cost-effectiveness of achieving increases in the use of oral rehydration solution and zinc supplementation in the management of acute diarrhea in children under 5 years through social franchising. The study uses cost and outcome data from an initiative by Population Services International (PSI) in 3 townships of Myanmar in 2010 to promote an ORS-Zinc product called ORASEL. The objective of this study was to determine the incremental cost-effectiveness of a strategy to promote ORS-Z use through private sector franchising compared to standard government and private sector practices. Costing from a societal perspective included program, provider, and household costs for the 2010 calendar year. Program costs including ORASEL program launch, distribution, and administration costs were obtained through a retrospective review of financial records and key informant interviews with staff in the central Yangon office. Household out of pocket payments for diarrheal episodes were obtained from a household survey conducted in the study area and additional estimates of household income lost due to parental care-giving time for a sick child were estimated. Incremental cost-effectiveness relative to status quo conditions was calculated per child death and DALY averted in 2010. Health effects included deaths and DALYs averted; the former modeled based on coverage estimates from a household survey that were entered into the Lives Saved Tool (LiST). Uncertainty was modeled with Monte Carlo methods. Based on the model, the promotional strategy would translate to 2.85 (SD 0.29) deaths averted in a community population of 1 million where there would be 81,000 children under 5 expecting 48,373 cases of diarrhea. The incremental cost effectiveness of the franchised approach to improving ORASEL coverage is estimated at a median $5,955 (IQR: $3437-$7589) per death averted and $214 (IQR: $127-$287) per discounted DALY averted. Investing in developing a network of private sector providers and keeping them stocked with ORS-Z as is done in a social franchise can be a highly cost-effective in terms of dollars per DALY averted.


[Oral magnesium supplementation: an adjuvant alternative to facing the worldwide challenge of type 2 diabetes?].
In the search for answers that contribute to the metabolic control of patients with diabetes and the primary prevention of the disease, we performed a review of the evidence from cohort studies on the relationship between serum and/or magnesium intake with the risk of developing type 2 diabetes as well as of clinical trials on the efficacy of oral magnesium salts on reducing glycemia. An electronic search using the databases MEDLINE, EMBASE, and Cochrane Controlled Trials Register, updated to September 30, 2013, was performed. A total of seven cohort studies (24,388 persons/year) show unequivocally that magnesium intake is associated with decreased risk of developing type 2 diabetes; two studies (13,076 persons/year) indicate that low magnesium intake is not associated with the risk of diabetes; one study (8,735 persons/year) shows that hypomagnesemia is associated with the development of impaired glucose metabolism. A total of 11 randomized controlled trials were identified; five show the effectiveness of oral magnesium salts in reducing glycemia in high-risk subjects and six studies carried out in patients with type 2 diabetes show inconsistent results. Magnesium intake in the customary diet of subjects of the general population and the high-risk groups and/or oral magnesium supplementation is recommended for the prevention of diabetes. The efficacy of oral magnesium supplementation in the reduction of glucose levels in type 2 diabetic patients is inconsistent.


The use of rhythmic auditory cues to influence gait in patients with Parkinson's disease, the differential effect for freezers and non-freezers, an explorative study.
To study the effect of rhythmic auditory cues on gait in Parkinson's disease subjects with and without freezing and in controls. A volunteer sample of 20 patients (10 freezers, 10 non-freezers) and 10 age-matched controls performed five randomized cued walking conditions in a gait-laboratory. Auditory cues were administered at baseline frequency, at an increased step frequency of 10 and 20% above baseline and at a decreased step frequency of 10 and 20% below baseline. Mean step frequency, walking speed, stride length and double support duration were collected. Rhythmical auditory cueing induced speed changes in all subjects. Stride length was not influenced by rhythmical auditory cues in controls, whereas patients showed a larger stride length in the -10% condition (p < 0.01). Freezers and non-freezers showed the same response to rhythmical auditory cues. Within group analysis for stride length showed different cueing effects. Stride length decreased at the +10% condition for freezers (p < 0.05), whereas it increased for non-freezers. This study points to fact that physiotherapists might need to carefully adjust the cueing frequency to the needs of patients with and without freezing. On the basis of the present results we recommend to lower the frequency setting for freezers, whereas for non-freezers an increase of up to +10% may have potential therapeutic use.


MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes.
Genome-wide association studies (GWAS) can identify common alleles that contribute to complex disease susceptibility. Despite the large number of SNPs assessed in each study, the effects of most common SNPs must be evaluated indirectly using either genotyped markers or haplotypes thereof as proxies. We have previously implemented a computationally efficient Markov Chain framework for genotype imputation and haplotyping in the freely available MaCH software package. The approach describes sampled chromosomes as mosaics of each other and uses available genotype and shotgun sequence data to estimate unobserved genotypes and haplotypes, together with useful measures of the quality of these estimates. Our approach is already widely used to facilitate comparison of results across studies as well as meta-analyses of GWAS. Here, we use simulations and experimental genotypes to evaluate its accuracy and utility, considering choices of genotyping panels, reference panel configurations, and designs where genotyping is replaced with shotgun sequencing. Importantly, we show that genotype imputation not only facilitates cross study analyses but also increases power of genetic association studies. We show that genotype imputation of common variants using HapMap haplotypes as a reference is very accurate using either genome-wide SNP data or smaller amounts of data typical in fine-mapping studies. Furthermore, we show the approach is applicable in a variety of populations. Finally, we illustrate how association analyses of unobserved variants will benefit from ongoing advances such as larger HapMap reference panels and whole genome shotgun sequencing technologies.


Disease mapping via negative binomial regression M-quantiles.
We introduce a semi-parametric approach to ecological regression for disease mapping, based on modelling the regression M-quantiles of a negative binomial variable. The proposed method is robust to outliers in the model covariates, including those due to measurement error, and can account for both spatial heterogeneity and spatial clustering. A simulation experiment based on the well-known Scottish lip cancer data set is used to compare the M-quantile modelling approach with a disease mapping approach based on a random effects model. This suggests that the M-quantile approach leads to predicted relative risks with smaller root mean square error. The paper concludes with an illustrative application of the M-quantile approach, mapping low birth weight incidence data for English Local Authority Districts for the years 2005-2010.


Randomized community-level HIV prevention intervention trial for men who drink in South African alcohol-serving venues.
South African alcohol-serving establishments (i.e., shebeens) offer unique opportunities to reduce HIV risks among men who drink. To test an individual- and a social structural-level HIV prevention intervention for men who drink in shebeens. Twelve matched pairs of township neighbourhoods were randomized to receive either (i) an HIV prevention intervention (guided by Social Action Theory) to reduce sexual risk and increase risk reduction communication in social networks, or (ii) an attention-matched control intervention that focused on the prevention of relationship violence. At the individual level, the interventions delivered skills building workshops focused on sexual risk reduction. At the social structural level, the intervention aimed to increase conversations about safer sex among men in the shebeens, distributed small media and implemented community educational events. Individual-level outcomes were assessed by following the workshop cohorts for 1 year (N = 984), and community-level outcomes were examined through cross-sectional community surveys conducted for 1 year in the shebeens (N = 9,678). Men in the HIV prevention workshops demonstrated greater condom use, more HIV prevention-oriented conversations and greater perceptions of safer sex norms than men in the comparison workshops. Changes at the community level demonstrated significant differences in condom use, although the pattern was not consistent over time. Multi-level interventions that target men who drink in South African shebeens may help reduce risks for HIV and other sexually transmitted infections.


Epidemic of Serratia marcescens bacteremia in a cardiac intensive care unit.
From 16 July through 27 September 1988, seven cases of nosocomial Serratia marcescens bacteremia occurred in a cardiac care unit. In all seven case patients, S. marcescens was isolated from blood cultures. Two of the seven had other microorganisms identified in the blood culture in which S. marcescens was recovered; one had Enterobacter cloacae, and one had Klebsiella pneumoniae. A case-control study was conducted to identify risk factors for bloodstream infection. Case patients were more likely than controls to have been exposed to an intra-aortic balloon pump pressure transducer (7 of 7 versus 6 of 21; P = 0.001) and to a pulmonary arterial pressure transducer (7 of 7 versus 8 of 21; P = 0.005). Cultures of in-use and in-storage transducers revealed bacterial contamination of the pressure-sensitive membranes of the transducers. S. marcescens blood culture isolates obtained from five of the seven case patients, as well as six S. marcescens isolates from cultured transducers, belonged to serotypes Oundetermined:H1 and Oundetermined:H18. E. cloacae isolates from one case patient and from two stored and two in-use transducers had identical antimicrobial suceptibility patterns. Review of cardiac care unit disinfection practices revealed that the transducers were not processed with high-level disinfection or sterilization between patient uses. We concluded that the transducers had served as reservoirs for this outbreak of bloodstream infection. Because intra-aortic balloon pumps with pressure transducers are being used more frequently in the management of critically ill cardiac patients, their role as infectious reservoirs should be considered in the investigation of nosocomial bacteremia.


Mentoring: Positively Influencing Job Satisfaction and Retention of New Hire Nurse Practitioners.
The purpose of study was to determine whether mentoring based on Watson's Caring Model positively influences nurse practitioner (NP) job satisfaction. This nonexperimental mixed-methods study utilized an online survey, administered through Qualtrics containing demographic and mentoring variables. Job satisfaction results were obtained from the Misener Nurse Practitioner Job Satisfaction Scale (MNPJSS). Also, open-ended questions regarding mentoring were reported. There was a 54% response rate in which 37 of the 69 participants responded (n = 37), with statistical significance set at p < .05. All or 100% of participants reported that the mentor experience/relationship positively influenced job satisfaction. Scores from the MNPJSS ranged from 141 to 246, with a mean of 195.26 (SD = 28.29) corresponding to "minimally satisfied" or a mean of 4.44 on the 6-point scale. These results are similar to the MNPJSS score with a mean of 4.39. A mentoring experience can provide a positive environment, which can lead to increased job satisfaction. In turn, a higher level of satisfaction in the work environment can be associated with reduced turnover and improved retention and patient outcomes. Ultimately, a safer health care system will evolve and improve patient care and outcomes. Through Watson's Caring Model, a reciprocal relationship between the mentor and the mentee can provide a new NP hire a sense of community and direct availability. By experiencing a mentor relationship, job satisfaction can improve, which is a key factor in retaining NPs. As E-mentoring is a newer topic in nursing literature, further research is needed. Further studies could also review and develop one-on-one mentoring programs.


Candida albicans Transcriptional Profiling Within Biliary Fluid From a Patient With Cholangitis, Before and After Antifungal Treatment and Surgical Drainage.
We used ribonucleic acid sequencing to profile Candida albicans transcription within biliary fluid from a patient with cholangitis; samples were collected before and after treatment with fluconazole and drainage. Candida albicans transcriptomes at the infection site distinguished treated from untreated cholangitis. After treatment, 1131 C. albicans genes were differentially expressed in biliary fluid. Up-regulated genes were enriched in hyphal growth, cell wall organization, adhesion, oxidation reduction, biofilm, and fatty acid and ergosterol biosynthesis. This is the first study to define Candida global gene expression during deep-seated human infection. Successful treatment of cholangitis induced C. albicans genes involved in fluconazole responses and pathogenesis.


Did the paycheck protection program hit the target?
This paper provides a comprehensive assessment of financial intermediation and the economic effects of the Paycheck Protection Program (PPP), a large and novel small business support program that was part of the initial policy response to the COVID-19 pandemic in the US. We use loan-level microdata for all PPP loans and high-frequency administrative employment data to present three main findings. First, banks played an important role in mediating program targeting, which helps explain why some funds initially flowed to regions that were less adversely affected by the pandemic. Second, we exploit regional heterogeneity in lending relationships and individual firm-loan matched data to study the role of banks in explaining the employment effects of the PPP. We find the short- and medium-term employment effects of the program were small compared to the program's size. Third, many firms used the loans to make non-payroll fixed payments and build up savings buffers, which can account for small employment effects and likely reflects precautionary motives in the face of heightened uncertainty. Limited targeting in terms of who was eligible likely also led to many inframarginal firms receiving funds and to a low correlation between regional PPP funding and shock severity. Our findings illustrate how business liquidity support programs affect firm behavior and local economic activity, and how policy transmission depends on the agents delegated to deploy it.


Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: The Detroit cardiogenic shock initiative.
The 'Detroit Cardiogenic Shock Initiative' is a single-arm, multicenter study to assess the feasibility of early mechanical circulatory support (MCS) in patients who present with acute myocardial infarction complicated by cardiogenic shock (AMICS) who undergo percutaneous coronary intervention. Between July 2016 and February 2017, 4 metro Detroit sites participated in the study. The centers agreed to treat patients with AMICS using a mutually agreed-upon protocol emphasizing invasive hemodynamic monitoring and rapid initiation of MCS. Inclusion and exclusion criteria mimicked those from the 'SHOCK' trial with an additional exclusion criteria being use of intra-aortic balloon pump counter pulsation prior to MCS. A total of 41 consecutive patients were included. Patients had an average age of 65 ± 14 years, 71% were male and 59% of patients were admitted to the hospital in cardiogenic shock. Prior to receiving MCS, 93% of patients were on vasopressors or inotropes, 15% of patients had a witnessed out of hospital cardiac arrest, 27% of patients had an in-hospital cardiac arrest, and 17% were under active cardiopulmonary resuscitation while MCS was being implanted. In accordance to the protocol recommendation, 66% of patients had a MCS device inserted prior to PCI. Right heart catheterization and hemodynamic monitoring was performed in 83% of patients. Door to support times averaged 83 ± 58 minutes and 71% of patients were able to reduce the levels of inotropes and vasopressors within the first 24-hours of their index procedure. Pre-procedure cardiac power output (CPO) was 0.57 W and post-procedure CPO was 0.95 W, a 67% increase (p < 0.001). Survival to explant for the entire cohort was 85% a significant improvement from institutional historical controls (85% vs 51% p < 0.001) and survival to discharge was 76%. Centers who adopted a regional shock protocol emphasizing the delivery of early MCS with invasive hemodynamic monitoring can achieve rapid door to support times and can improve survival in patients who present with AMICS. Larger national studies will be needed to further validate this pilot feasibility study.


Bartonellosis in Ecuador: serosurvey and current status of cutaneous verrucous disease.
Human bartonellosis is a classically biphasic disease caused by infection with the alpha-2 Proteobacteria Bartonella bacilliformis, which is phylogenetically related to the etiologic agents of cat scratch disease, bacillary angiomatosis, and trench fever. In Ecuador, typical bartonellosis has remained endemic for the past century in highland provinces near the Peruvian border. During the past six years, public health officials have noted an increasing number of atypical cases in which monophasic verrucous cutaneous disease is the only clinical manifestation. Epidemiologic, immunologic, histopathologic, and molecular biological studies have confirmed the presence of sporadic, atypical bartonellosis in residents of the lowland province of Manabi, where archeologic evidence exists of bartonellosis in pre-Colombian times. Between 1987 and 1995, 11 cases of cutaneous bartonellosis were investigated and serologic studies were done on 224 persons from five villages, two lowland and three highland. In the lowland village of Pajan in the province of Manabi, there was a 21% seropositivity proportion in contacts of index cases. These combined data suggest that bartonellosis is significantly under-reported due to the existence of mild clinical disease, possibly associated with less virulent bacterial strains, which are now disseminating or re-emerging in previously disease-free areas.


Assessment of agreement among diplomates of the American College of Veterinary Anesthesia and Analgesia for scoring the recovery of horses from anesthesia by use of subjective grading scales and development of a system for evaluation of the recovery of horses from anesthesia by use of accelerometry.
OBJECTIVE To evaluate agreement among diplomates of the American College of Veterinary Anesthesia and Analgesia for scores determined by use of a simple descriptive scale (SDS) or a composite grading scale (CGS) for quality of recovery of horses from anesthesia and to investigate use of 3-axis accelerometry (3AA) for objective evaluation of recovery. ANIMALS 12 healthy adult horses. PROCEDURES Horses were fitted with a 3AA device and then were anesthetized. Eight diplomates evaluated recovery by use of an SDS, and 7 other diplomates evaluated recovery by use of a CGS. Agreement was tested with κ and AC1 statistics for the SDS and an ANOVA for the CGS. A library of mathematical models was used to map 3AA data against CGS scores. RESULTS Agreement among diplomates using the SDS was slight (κ = 0.19; AC1 = 0.22). The CGS scores differed significantly among diplomates. Best fit of 3AA data against CGS scores yielded the following equation: RS = 9.998 × SG0.633 × ∑UG0.174, where RS is a horse's recovery score determined with 3AA, SG is acceleration of the successful attempt to stand, and ∑UG is the sum of accelerations of unsuccessful attempts to stand. CONCLUSIONS AND CLINICAL RELEVANCE Subjective scoring of recovery of horses from anesthesia resulted in poor agreement among diplomates. Subjective scoring may lead to differences in conclusions about recovery quality; thus, there is a need for an objective scoring method. The 3AA system removed subjective bias in evaluations of recovery of horses and warrants further study.


Results of curative gastrectomy for carcinoma of the distal third of the stomach.
Carcinoma of the distal stomach metastasizes to lymph nodes along the bile duct, pancreatic head, and duodenum. We reviewed the results of patients who underwent operation for carcinoma of the stomach, and placed special emphasis on survival related to lymph node metastasis. We conducted a prospective study of 258 consecutive patients with adenocarcinoma of the distal third of the stomach who underwent curative gastrectomies. Most of the patients (193 [75 percent]) had advanced cancer (extension beyond the submucosa). A subtotal gastrectomy was the procedure most commonly performed (89 percent). Combined organ resection was performed in 100 patients (39 percent). The operative morbidity was 17 percent; the most frequent complications were chylous leakage, anastomotic insufficiency, and intra-abdominal infection. Ninety-four patients (36 percent) had tumor recurrence, with local recurrence occurring in 45 patients. In 40 of the 45 cases, the local recurrence resulted from remnant lymph nodes (LNs), or soft tissues in the gastric bed. Lymph node metastases were observed in 152 patients (59 percent). Excluding five patients (2 percent) who died, the overall five-year cumulative survival rate was 53 percent. The five year survival rate was 98 percent for patients with TNM stage I disease; 68 percent for patients with stage II disease; 40 percent for patients with stage III disease; and 10 percent for patients with stage IV disease. The survival rate for patients with n0, n1, n2, and n3 disease was respectively 92 percent, 45 percent, 30 percent, and 20 percent. For patients with metastatic LNs in the hepatoduodenal ligament, the five-year survival rate was 20 percent. These data suggest that survival rate relates to the extent of LN metastasis. It appears that systematic lymph node dissection may have a beneficial effect. However, the efficacy of radical lymph node dissection can only be determined by prospective, randomized clinical trials with a proper study design.


Neuroprotective effects of coenzyme Q10 on paraquat-induced Parkinson's disease in experimental animals.
Parkinson's disease (PD) affects ∼1-2% of the elderly population. Development of a neuroprotective therapy that may be initiated early in the course of the disease to retard/prevent disease progression is highly desirable. This study aimed to investigate prophylactic treatment with coenzyme Q10 (CoQ10) before paraquat (PQ) exposure, a herbicide known to increase the risk for PD, to attain neuroprotection. In addition, therapeutic intervention with CoQ10 in mice already exposed to PQ (24 h) might halt ongoing neurodegeneration and behavioural deterioration. PD was induced experimentally in mice by an injection of PQ (10 mg/kg, intraperitoneal), twice a week for 3 consecutive weeks, either before or after the initiation of treatment with CoQ10 (200 mg/kg). The results of the sustained supplementation with CoQ10, prophylactically and therapeutically, were compared with L-DOPA (100 mg/kg). A battery of behavioural tests was performed, in addition to estimation of protein carbonyl in the brain. CoQ10 elicited a remarkable improvement in most of the behavioural tests and decreased protein carbonyl content in the brain, particularly when it was initiated before rather than after PQ induction of PD. Therefore, CoQ10, which protects against mitochondrial damage, may be beneficial in slowing the progression of PD, particularly when initiated as prophylactic treatment.


Burden of Influenza in 4 Ecologically Distinct Regions of Peru: Household Active Surveillance of a Community Cohort, 2009-2015.
There are limited data on the burden of disease posed by influenza in low- and middle-income countries. Furthermore, most estimates of influenza disease burden worldwide rely on passive sentinel surveillance at health clinics and hospitals that lack accurate population denominators. We documented influenza incidence, seasonality, health-system utilization with influenza illness, and vaccination coverage through active community-based surveillance in 4 ecologically distinct regions of Peru over 6 years. Approximately 7200 people in 1500 randomly selected households were visited 3 times per week. Naso- and oropharyngeal swabs were collected from persons with influenza-like illness and tested for influenza virus by real-time reverse-transcription polymerase chain reaction. We followed participants for 35353 person-years (PY). The overall incidence of influenza was 100 per 1000 PY (95% confidence interval [CI], 97-104) and was highest in children aged 2-4 years (256/1000 PY [95% CI, 236-277]). Seasonal incidence trends were similar across sites, with 61% of annual influenza cases occurring during the austral winter (May-September). Of all participants, 44 per 1000 PY (95% CI, 42-46) sought medical care, 0.7 per 1000 PY (95% CI, 0.4-1.0) were hospitalized, and 1 person died (2.8/100000 PY). Influenza vaccine coverage was 27% among children aged 6-23 months and 26% among persons aged ≥65 years. Our results indicate that 1 in 10 persons develops influenza each year in Peru, with the highest incidence in young children. Active community-based surveillance allows for a better understanding of the true burden and seasonality of disease that is essential to plan the optimal target groups, timing, and cost of national influenza vaccination programs.


Repeat testing is essential when estimating chronic kidney disease prevalence and associated cardiovascular risk.
Investigations into chronic kidney disease (CKD) and cardiovascular disease in the CKD population may be misleading as they are often based on a single test of kidney function. To determine whether repeat testing at 3 months to confirm a diagnosis of CKD impacts on the estimated prevalence of CKD and the estimated 10-year general cardiovascular risk of the CKD population. Blood and urine samples from presumed healthy volunteers were analysed for evidence of CKD on recruitment and again 3 months later. Estimated 10-year cardiovascular risk was calculated using criteria determined by the Framingham study. Preliminary study: 512 volunteers were screened for CKD. Of the initial results, 206 indicated CKD or eGFR within one standard deviation of abnormal, and 142 (69%) of these were retested. Validation study: 528 volunteers were recruited and invited to return for repeat testing. A total of 214 (40.5%) participants provided repeat samples. A single test indicating CKD had a positive predictive value of 0.5 (preliminary) and 0.39 (validation) for repeat abnormalities 3 months later. Participants with CKD confirmed on repeat testing had a significant increase in estimated 10-year cardiovascular risk over the population as a whole (preliminary: 16.5 vs. 11.9%, P < 0.05; validation: 18.1 vs. 9.2%, P < 0.01). Participants with a solitary test indicating CKD had no elevation in cardiovascular risk. Repeat testing for CKD after 3 months significantly reduces the estimated prevalence of disease and identifies a population with true CKD and a cardiovascular risk significantly in excess of the general population.


Regular analgesic use and risk of endometrial cancer.
Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but thus far, no previous research has focused on the role of aspirin in endometrial cancer etiology. We conducted a hospital-based case-control study of 427 women with primary, incident endometrial cancer, and 427 age- and residence-matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiologic questionnaire. Women who reported analgesic use at least once a week for at least 6 months were classified as regular users and served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI). Compared with nonusers, regular aspirin users were not at reduced risk of endometrial cancer (adjusted OR, 0.91; 95% CI, 0.66-1.26), nor were women with the highest frequency, duration, or cumulative lifetime aspirin use. When the sample was divided by body mass index status, regular aspirin use was not associated with risk among women classified as normal weight or overweight, but a significant risk reduction was seen for obese women (adjusted OR, 0.50; 95% CI, 0.27-0.92). Significant decreases in risk were also observed for obese women with the greatest frequency, duration, and cumulative aspirin use. No significant associations in the overall sample or among obese women were noted for acetaminophen use. We observed no evidence of an overall chemoprotective effect of aspirin on endometrial cancer risk, but the significant risk reductions among obese women warrant further investigation.


Effect of predicted low suspend pump treatment on improving glycaemic control and quality of sleep in children with type 1 diabetes and their caregivers: the QUEST randomized crossover study.
In attempting to achieve optimal metabolic control, the day-to-day management is challenging for a child with type 1 diabetes (T1D) and his family and can have a major negative impact on their quality of life. Augmenting an insulin pump with glucose sensor information leads to improved outcomes: decreased haemoglobin A1c levels, increased time in glucose target and less hypoglycaemia. Fear of nocturnal hypoglycaemia remains pervasive amongst parents, leading to chronic sleep interruption and lack of sleep for the parents and their children. The QUEST study, an open-label, single-centre randomized crossover study, aims to evaluate the impact on time in target, in hypoglycaemia and hyperglycaemia and the effect on sleep and quality of life in children with T1D, comparing a sensor-augmented pump (SAP) with predictive low glucose suspend and alerts to the use of the same insulin pump with a flash glucose measurement (FGM) device not interacting with the pump. Subjects meeting the inclusion criteria are randomized to treatment with the SAP or treatment with an insulin pump and independent FGM for 5 weeks. Following a 3-week washout period, the subjects cross over to the other study arm for 5 weeks. During the week before and in the last week of treatment, the subjects and one of their caregivers wear a sleep monitor in order to obtain sleep data. The primary endpoint is the between-arm difference in percentage of time in glucose target during the final 6 days of each treatment arm, measured by a blinded continuous glucose measurement (CGM). Additional endpoints include comparison of quantity and quality of sleep as well as quality of life perception of the subjects and one of their caregivers in the two different treatment arms. Recruitment started in February 2017. A total of 36 patients are planned to be randomized. The study recruitment was completed in April 2018. With this study we will provide more information on whether insulin pump treatment combined with more technology (SmartGuard® feature and alerts) leads to better metabolic control. The inclusion of indicators on quality of sleep with less sleep interruption, less lack of sleep and perception of quality of life in both children and their primary caregivers is essential for this study and might help to guide us to further treatment improvement. ClinicalTrials.gov, NCT03103867 . Registered on 6 April 2017.


A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.
MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.


Non-compliance with contact lens wear and care practices: a comparative analysis.
To compare the effects of existing patient awareness of lens-related complications and underlying risk factors on actual patient behavior during contact lens wear and care practices in two different clinical study populations. Established contact lens wearers (n = 281) completed an anonymous written questionnaire on presenting to their habitual eye care practitioner in the Dallas-Fort Worth metroplex. Data were analyzed and compared against a second study population, which comprised established contact lens wearers (n = 152) who were sequentially evaluated after their routine contact lens examination at the University of Texas Southwestern Medical Center at Dallas, TX (UTSW). All patients were questioned regarding his or her lens care practices and knowledge of complications and risk factors associated with contact lens wear. Fifty-eight percent of patients in the general community could identify by name a complication associated with lens wear compared with 91% within the medical center. The most frequent complications reported were related to comfort and handling (72%, Dallas-Fort Worth) and infection (47%, UTSW). The majority of patients could correctly identify risk factors associated with lens-related complications; awareness for topping-off solutions, tap water exposure, and hygiene varied between groups. Overall, 85% of patients perceived themselves as compliant with their lens wear and care practices. Using a standard scoring model to determine actual compliance, 2% of patients demonstrated good compliance; however, only 0.4% of patients were fully compliant with contact lens wear and care practices. The data reveal some study bias in complication and risk awareness between populations; however, despite this limitation, a significant proportion of patients exhibited actual non-compliant behavior despite acknowledged awareness of risk. Although most patients consider themselves to be complying with standard practitioner guidelines for lens wear and care practices, essentially all contact lens wearing patients exhibit behavioral non-compliance with resulting increased risk for significant complications.


Global discrepancies in the diagnosis, surgical management, and investigation of femoroacetabular impingement.
The purpose of this study was to review the global pattern of surgical management of femoroacetabular impingement (FAI), particularly in diagnosis, outcome measurement, and management. We performed a systematic search in duplicate for surgical studies addressing FAI published up to June 2013. Study parameters, including sample size, study location, surgical intervention technique, diagnostic imaging, outcome measures used, sex distribution, and level of evidence, were obtained. The number of trials and cumulative sample size were analyzed. The surgical interventions, sex distribution, outcome measures, and diagnostic imaging used were compared between geographic regions. We identified 105 studies reporting surgical interventions for FAI. Most studies were completed in North America (52 studies, 3,629 patients) and in Europe (44 studies, 3,745 patients). Asia (3 studies, 49 patients) and Oceania (6 studies, 394 patients) had smaller contributions. There were no studies from South America or Africa. Most research performed in North America, Europe, and Oceania investigated arthroscopic FAI surgery (55% of studies) followed by surgical dislocation (33%), and miniopen (15%) and combined approaches (8%). Methods of diagnosis were consistent worldwide, with radiography being the mainstay of diagnosis (84% of studies). Case series were the most common type of study globally (75% of studies). Outcome measures varied by region; Harris hip scores were most common in North America, Oceania, and Asia, whereas Non-Arthritic Hip Scores and Western Ontario McMaster scores predominated in Europe. Global surgical trends for FAI show a predominance of North American and European studies, studies of lower level evidence, and inconsistent use of outcome measures. However, patterns of diagnostic imaging, sex proportions, and predominance of arthroscopic techniques are consistent worldwide. Future research should focus on development of reliable validated outcome measures and international collaboration to conduct high-quality research and improve our understanding of FAI diagnosis and management. Level IV, systematic review of Level I-IV studies.


Enablers and Barriers to Implementing ICU Follow-Up Clinics and Peer Support Groups Following Critical Illness: The Thrive Collaboratives.
Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. Clinicians from 21 sites. Ten enablers and nine barriers to implementation of "ICU follow-up clinics" were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of "peer support groups" were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles.


A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate.
Diphosphoinositol phosphates (PP-InsPs) are inositol phosphates (InsPs) that contain PP (diphosphate) groups. Converting a phosphate group in an InsP into a diphosphate has been reported to enhance affinity for some binding proteins. We synthesised 1-PP-Ins(4,5)P2, the first diphosphate analogue of the intracellular signalling molecule InsP3, and examined its effects on InsP3 receptors, which are intracellular Ca2+ channels. 1-PP-Ins(4,5)P2 was indistinguishable from InsP3 in its ability to bind to and activate type 1 InsP3 receptors, indicating that the diphosphate modification of InsP3 affected neither affinity nor efficacy. Nevertheless, 1-PP-Ins(4,5)P2 is the most potent 1-phosphate modified analogue of InsP3 yet identified. PP-InsPs are generally hydrolysed by diphosphoinositol phosphate phosphohydrolases (DIPPs), but 1-PP-Ins(4,5)P2 was not readily metabolised by human DIPPs. Differential scanning fluorimetry showed that 1-PP-Ins(4,5)P2 stabilises DIPP proteins, but to a lesser extent than naturally occurring substrates 1-PP-InsP5 and 5-PP-InsP5. The non-hydrolysable InsP7 analogues 1-PCP-InsP5 and 5-PCP-InsP5 showed comparable stabilising abilities to their natural counterparts and may therefore be promising substrate analogues for co-crystallisation with DIPPs.


Partial volume correction for quantitative CEST imaging of acute ischemic stroke.
Contributions of cerebrospinal fluid (CSF) have not been previously taken into account in the quantification of APT CEST effects, and correction for the dilution of CEST effects by CSF may allow for more robust measurement of CEST signals. The objective of this study was to compare the robustness of a partial volume (PV) correction model against a standard (4-pool) multi-pool model as far as their ability to quantify CEST effects in healthy, normal, and pathological tissue. MRI data from 12 patients presenting with ischemic stroke, and 6 healthy subjects, were retrospectively analyzed. CEST signals derived from a 4-pool model and a PV correction model were compared for repeatability and pathological tissue contrast. The effect of PV correction (PVC) was assessed within 3 ranges of tissue PV estimate (PVE): high PVE voxels, low PVE voxels, and the whole slice. In voxels with a high tissue PVE, PV correction did not make a significant difference to absolute APTR* . In low PVE voxels, the PVC model exhibited a significantly decreased ischemic core signal. The PVC measures exhibited higher repeatability between healthy subjects (4 pools: 3.4%, PVC: 2.4%) while maintaining a similar ischemic core CNR (0.7) to the 4-pool model. In whole slice analysis it was found that both models exhibited similar results. PV correction yielded a measure of APT effects that was more repeatable than standard 4-pool analysis while achieving a similar CNR in pathological tissue, suggesting that PV-corrected analysis was more robust at low values of tissue PVE.


Rethinking screening for breast cancer and prostate cancer.
After 20 years of screening for breast and prostate cancer, several observations can be made. First, the incidence of these cancers increased after the introduction of screening but has never returned to prescreening levels. Second, the increase in the relative fraction of early stage cancers has increased. Third, the incidence of regional cancers has not decreased at a commensurate rate. One possible explanation is that screening may be increasing the burden of low-risk cancers without significantly reducing the burden of more aggressively growing cancers and therefore not resulting in the anticipated reduction in cancer mortality. To reduce morbidity and mortality from prostate cancer and breast cancer, new approaches for screening, early detection, and prevention for both diseases should be considered.


Molecular and genetic aspects of odontogenic tumors: a review.
Odontogenic tumors contain a heterogeneous collection of lesions that are categorized from hamartomas to benign and malignant neoplasms of inconstant aggressiveness. Odontogenic tumors are usually extraordinary with assessed frequency of short of 0.5 cases/100,000 population for every year. The lesions such as odontogenic tumors are inferred from the components of the tooth-structuring contraption. They are discovered solely inside the maxillary and mandibular bones. This audit speaks to experiences and cooperation of the molecular and genetic variations connected to the development and movement of odontogenic tumors which incorporate oncogenes, tumor-silencer genes, APC gene, retinoblastoma genes, DNA repair genes, onco-viruses, development components, telomerase, cell cycle controllers, apoptosis-related elements, and regulators/conttrollers of tooth development. The reasonable and better understanding of the molecular components may prompt new ideas for their detection and administrating a better prognosis of odontogenic tumors.


Respiratory Support in COVID-19 Patients, with a Focus on Resource-Limited Settings.
The ongoing novel coronavirus disease (COVID-19) pandemic is threatening the global human population, including in countries with resource-limited health facilities. Severe bilateral pneumonia is the main feature of severe COVID-19, and adequate ventilatory support is crucial for patient survival. Although our knowledge of the disease is still rapidly increasing, this review summarizes current guidance on the best provision of ventilatory support, with a focus on resource-limited settings. Key messages include that supplemental oxygen is a first essential step for the treatment of severe COVID-19 patients with hypoxemia and should be a primary focus in resource-limited settings where capacity for invasive ventilation is limited. Oxygen delivery can be increased by using a non-rebreathing mask and prone positioning. The presence of only hypoxemia should in general not trigger intubation because hypoxemia is often remarkably well tolerated. Patients with fatigue and at risk for exhaustion, because of respiratory distress, will require invasive ventilation. In these patients, lung protective ventilation is essential. Severe pneumonia in COVID-19 differs in some important aspects from other causes of severe pneumonia or acute respiratory distress syndrome, and limiting the positive end-expiratory pressure level on the ventilator may be important. This ventilation strategy might reduce the currently very high case fatality rate of more than 50% in invasively ventilated COVID-19 patients.