Sepsis Care Pathway 2019.
Background: Sepsis, a medical emergency and life-threatening disorder, results from abnormal host response to infection that leads to acute organ dysfunction1. Sepsis is a major killer across all ages and countries and remains the most common cause of admission and death in the Intensive Care Unit (ICU)2. The true incidence remains elusive and estimates of the global burden of sepsis remain a wild guess. One study suggested over 19 million cases and 5 million sepsis-related deaths annually3. Addressing the challenge, the World Health Assembly of the World Health Organisation (WHO) passed a resolution on better prevention, diagnosis, and management of sepsis4. Current state of sepsis guidelines: Despite thousands of articles and hundreds of trials, sepsis remains a major killer. The cornerstones of sepsis care remain early recognition, adoption of a systematic evidence-based bundle of care, and timely escalation to higher level of care. The bundle approach has been advocated since 2004 but underwent major modifications in subsequent years with more emphasis on the time-critical nature of sepsis and need to restore physiological variables within one hour of recognition. A shift from a three and six-hour bundle to one-hour bundle has been recommended5. This single hour approach has been faced with an outcry and been challenged6-8. One size never fits all: Over several decades, the individual components of the sepsis bundle have not changed. Encountering a patient with suspected sepsis, one should measure lactate, obtain blood cultures, swiftly administer broad spectrum antimicrobials and fluids, and infuse vasopressors. A critical question arises: should we do this for all patients? Sepsis is not septic shock and guidelines did not make distinctive recommendations for each. Septic patients will present differently with some having more subtle signs and symptoms. Phenotypically, we do not know which patient with infection will develop a dysregulated host response and will succumb to sepsis and/or shock6-8. The existing bundle lacks high quality evidence to support its recommendations and a blanket implementation for all patients with 'suspected' sepsis could be harmful7. Indeed, a significant reduction of sepsis and septic shock in Australia and New Zealand was observed in a bundle-free region8. Emergency Department (ED) challenges: Upon arrival in the ED, patients will be triaged. This is 'time zero'5. Those with hypotension and hypoperfusion will be easily recognised and at most need to receive emergent care. Sepsis, per se, may not manifest clear cut signs and expertise to identify it is required. Those with non-specific symptoms may trigger an early warning scoring system and receive unnecessary antimicrobials and a large volume of intravenous (IV) fluids. Both therapies are not without significant side effects. Putting pressure on ED physicians to implement the 60-minute bundle without individualisation of care puts our patients at risk6-8. Diagnostic challenges: Given the heterogenous nature and diverse pathobiological pathways, sepsis diagnosis can be challenging and both over and under-treatment can result. Established biomarkers such as procalcitonin and C-reactive protein lack specificity to rule out infection as the cause of inflammation. Currently, no laboratory test or biomarker helps predict which patients with infection or inflammation will develop organ dysfunction. A dire need for a specific sepsis biomarker exists10. Modern molecular-based technologies are evolving and utilise polymerase chain reaction (PCR), nanotechnology, and microfluidics for point-of-care testing. Some devices identify causative microorganisms and their sensitivity in less than an hour10. The bundle components: Catecholamines along with IV fluids are indicated to restore perfusion. However, inadvertent side effects may arise, especially at higher doses. Anti-adrenergic ß-blockers improve cardiac performance, enhance receptor responsiveness, and possess anti-inflammatory action. All are desirable in patients with septic shock11. One randomised trial showed beneficial and protective effects of ß-blockers in septic shock. Rapidly acting titratable agents should be used in conjunction with appropriate hemodynamic monitoring and after adequate volume resuscitation. There is no consensus on target heart rate but an arbitrary cut off of 80-95 beats per minute is reasonable11. Fluid resuscitation is the cornerstone of sepsis management. There is also compelling evidence that too much fluid is bad. Starch-based colloids should not be used in septic shock. Albumin is an alternative when large volumes are required but is not appropriate in traumatic brain injury. Balanced, less chloride and less acidic crystalloids are safer for the kidneys and are preferred over normal saline. Doses of IV fluids should be tailored to the patient's condition and a 30 ml/kg recommendation should be reviewed.12 Effective sepsis management requires adequate dosing of antimicrobials. Significant alteration of pharmacokinetics and pharmacodynamics is characteristic of septic shock13. Accurate and effective dosing is challenging particularly in patients with multiple comorbidities and those receiving extracorporeal organ support. Underdosing results in treatment failure, whilst overdosing leads to toxicity and the risk of developing multi-drug resistant organisms13. An individualised approach supported by therapeutic drug monitoring is suggested to ensure clinical efficacy13. Sepsis research: The search for a cure for sepsis is ongoing. A large prospective, randomised two-arm, parallel group study aims to recruit over 200 patients with septic shock across critical care units in Qatar. Evaluation of Hydrocortisone, Vitamin C, and Thiamine (HYVITS) examines the safety and efficacy of this triple therapy14. Sepsis in the young patient: Children are particularly vulnerable to sepsis. 1 in 6 children admitted with septic shock to ICU will die. As the majority of paediatric sepsis cases are community acquired, there is a strong need to raise awareness both for families and primary healthcare providers. Akin to adults, a bundle-approach to paediatric sepsis is strongly encouraged. National programs for paediatric sepsis have been established15. The Qatar paediatric multidisciplinary sepsis program was established under the umbrella of the adult programme in 2017. A structured and standardised approach to sepsis across all neonate and paediatric facilities has been developed and implemented. Improvement in timely sepsis recognition and administration of antimicrobials within the golden hour has been observed. The program aims to achieve a 95% compliance to the paediatric sepsis bundle by the end of 2019. A screening tool and order set have been put in place and are presented in this special issue of Qatar Medical Journal16,17. Obstetric sepsis: Pregnancy and childbirth are risk factors for sepsis. Multi-organ failure and death can result from puerperal sepsis18. Sepsis is the direct and leading cause of maternal mortality in the UK19. Attention to maternal sepsis with a tailored approach is encouraged. The Qatar National Sepsis Program developed a sepsis care pathway for pregnant women and during their early post-partum period. Challenges in low socioeconomic societies: A broader, national -or better yet- a global approach to further sepsis management and outcome should be considered. There are a number of significant challenges to address. One such challenge is the inconsistency of the operational definition and diagnostic approaches for sepsis including coding and documentation1,3. Significant deficiencies in healthcare systems have been highlighted by sepsis. This is most obvious in medium- and low-income countries. A major limitation to effective sepsis management is inadequate medical staffing and poor knowledge and awareness of sepsis. Both have a negative impact on sepsis outcome3. Poor medical facilities in many countries pose significant challenges to sepsis care. Lack of critical care capacity - a global phenomenon - has been linked to poor outcome of sepsis cases and septic shock. This could be attributed to provision of suboptimal critical care, monitoring and critical interventions outside of the ICU. ICU availability is subject to inconsistency and inequity.2,3 Lack of adequate surgical capacity to accomplish timely source control adversely affects sepsis management. This, unfortunately, in medium- and low-income countries, is accompanied by inadequate medical supplies, diagnostic capacity, and manpower which increases sepsis mortality and morbidity3. Global concerns: Antimicrobials are critical for sepsis care. A global concern is the development of multi-drug resistant organisms and the lack of novel antimicrobials and this adds pressure on those caring for septic patients. Effective antimicrobials should be utilised to eradicate infections. Misuse, inadequacy, inferior agents, and lack of timely access to effective and affordable agents significantly hinders patient's recovery from sepsis2,3. Optimum sepsis outcome mandates attention to acute sepsis complications (e.g. acute renal or respiratory failure) as well as addressing post-discharge complications and disability. These challenging issues remain poorly studied or addressed3. Conclusion: Sepsis and septic shock are major global health concerns. Progress has been achieved in understanding this life-threatening syndrome at a biological, metabolic, and cellular level. Efforts should be coordinated to improve sepsis care. Better and more accurate diagnostics are needed and governments are encouraged to invest in sepsis research and care. More integrated, inclusive, and focused research is desperately needed. Public education and increased awareness among primary healthcare providers are also critical to improve sepsis outcome.


Sensitive Drone Mapping of Methane Emissions without the Need for Supplementary Ground-Based Measurements.
Methane (CH4) is one of the main greenhouse gas for which sources and sinks are poorly constrained and better capacity of mapping landscape emissions are broadly requested. A key challenge has been comprehensive, accurate, and sensitive emission measurements covering large areas at a resolution that allows separation of different types of local sources. We present a sensitive drone-based system for mapping CH4 hotspots, finding leaks from gas systems, and calculating total CH4 fluxes from anthropogenic environments such as wastewater treatment plants, landfills, energy production, biogas plants, and agriculture. All measurements are made on-board the drone, with no requirements for additional ground-based instruments. Horizontal flight patterns are used to map and find emission sources over large areas and vertical flight patterns for total CH4 fluxes using mass balance calculations. The small drone system (6.7 kg including batteries, sensors, loggers, and weather proofing) maps CH4 concentrations and wind speeds at 1 Hz with a precision of 0.84 ppb/s and 0.1 m/s, respectively. As a demonstration of the system and the mass balance method for a CH4 source that is difficult to assess with traditional methods, we have quantified fluxes from a sludge deposit at a wastewater treatment plant. Combining data from three 10 min flights, emission hotspots could be mapped and a total flux of 178.4 ± 8.1 kg CH4 d-1 was determined.


Cognitive functioning in young and middle-aged unmedicated out-patients with major depression: testing the effort and cognitive speed hypotheses.
Cognitive deficits are common in major depressive disorder, but their nature is unclear. The effort hypothesis states that performance on effortful tasks is disproportionately impaired compared with the performance on automatic tasks. The cognitive speed hypothesis states that depression is characterized by cognitive slowness, which is a source of cognitive dysfunctioning. The present study investigated both theories in unmedicated adult depressive patients. It was also investigated whether the cognitive deficits can be attributed to more general physical illness-related factors or specifically to depressive disorder. Thirty non-psychotic depressive out-patients were compared with 38 healthy control subjects and 25 patients with severe allergic rhinitis. The effects of group on more automatic and more effortful aspects of cognitive tasks measuring cognitive speed (Concept Shifting Task, Stroop Colour Word Test, Memory Scanning Test) and memory retrieval (Visual Verbal Learning Task, Verbal Fluency Test) were evaluated by MANCOVA. Age, sex, education and pre-morbid intelligence were treated as covariates. The depressive group had cognitive deficits in the automatic processing subtask of the Stroop, memory scanning and memory span. Performance on more effortful tasks was not impaired. Our results are more consistent with the cognitive speed hypothesis. Cognitive functioning in depressive disorder seems to be characterized by a reduced speed of information processing in automatic subtasks.


Mammalian hibernation: differential gene expression and novel application of epigenetic controls.
This review highlights current information about the regulatory mechanisms that govern gene expression during mammalian hibernation, in particular the potential role of epigenetic controls in coordinating the global suppression of transcription. Hibernation is characterized by long periods of deep torpor (when core body temperature drops to near ambient) that are interspersed with brief arousal periods back to euthermia. Entry into torpor requires coordinated controls which strongly suppress and reprioritize all metabolic functions, including global controls on both transcription and translation. At the same time, however, selected hibernation-specific genes are up-regulated under the control of specific transcription factors to support the torpid state; this includes genes that encode proteins involved in lipid fuel catabolism and in long term cytoprotection (e.g. antioxidants, chaperones). We evaluate the currently available information on global transcriptional suppression in hibernation and propose that epigenetic mechanisms such as DNA methylation, histone modification, SUMOylation and the actions of sirtuins play crucial roles in transcriptional suppression during torpor. Global controls providing translational suppression also occur during hibernation including reversible phosphorylation control of ribosomal initiation and elongation factors as well as polysome dissociation. We also present initial data that mRNA transcripts are regulated via inhibitory interactions with microRNA species during torpor and provide the first evidence of differential expression of miRNAs in hibernators. When taken together, these mechanisms provide hibernators with multiple layers of regulatory controls that achieve both global repression of gene expression and selected enhancement of genes/proteins that achieve the hibernation phenotype.


A multifunctional polymeric nanotheranostic system delivers doxorubicin and imaging agents across the blood-brain barrier targeting brain metastases of breast cancer.
Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases.


Chemical characterization of exhaled breath to differentiate between patients with malignant plueral mesothelioma from subjects with similar professional asbestos exposure.
Malignant pleural mesothelioma (MPM) is an aggressive tumour whose main aetiology is the long-term exposure to asbestos fibres. The diagnostic procedure of MPM is difficult and often requires invasive approaches; therefore, it is clinically important to find accurate markers for MPM by new noninvasive methods that may facilitate the diagnostic process and identify patients at an earlier stage. In the present study, the exhaled breath of 13 patients with histology-established diagnosis of MPM, 13 subjects with long-term certified professional exposure to asbestos (EXP) and 13 healthy subjects without exposure to asbestos (healthy controls, HC) were analysed. An analytical procedure to determine volatile organic compounds by sampling of air on a bed of solid sorbent and thermal desorption GC-MS analysis was developed in order to identify the compounds capable of discriminating among the three groups. The application of univariate (ANOVA) and multivariate statistical treatments (PCA, DFA and CP-ANN) showed that cyclopentane and cyclohexane were the dominant variables able to discriminate among the three groups. In particular, it was found that cyclohexane is the only compound able to differentiate the MPM group from the other two; therefore, it can be a possible marker of MPM. Cyclopentane is the dominant compound in the discrimination between EXP and the other groups (MPM and HC); then, it can be considered a good indicator for long-term asbestos exposure. This result suggests the need to perform frequent and thorough investigations on people exposed to asbestos in order to constantly monitor their state of health or possibly to study the evolution of disease over time.


Alternation of generations and experimental design: a guided-inquiry lab exploring the nature of the her1 developmental mutant of Ceratopteris richardii (C-Fern).
Inquiry-based labs have been shown to greatly increase student participation and learning within the biological sciences. One challenge is to develop effective lab exercises within the constraints of large introductory labs. We have designed a lab for first-year biology majors to address two primary goals: to provide effective learning of the unique aspects of the plant life cycle and to gain a practical knowledge of experimental design. An additional goal was to engage students regardless of their biology background. In our experience, plant biology, and the plant life cycle in particular, present a pedagogical challenge because of negative student attitudes and lack of experience with this topic. This lab uses the fern Ceratopteris richardii (C-Fern), a model system for teaching and research that is particularly useful for illustrating alternation of generations. This lab does not simply present the stages of the life cycle; it also uses knowledge of alternation of generations as a starting point for characterizing the her1 mutation that affects gametophyte sexual development. Students develop hypotheses, arrive at an appropriate experimental design, and carry out a guided inquiry on the mechanism underlying the her1 mutation. Quantitative assessment of student learning and attitudes demonstrate that this lab achieves the desired goals.


Amino acids and muscle loss with aging.
Aging is associated with a progressive loss of muscle mass (sarcopenia), which increases the risks of injury and disability. Although the mechanisms of sarcopenia are not clearly elucidated, age-associated alterations in the muscle anabolic response to nutritional stimuli and a decline in protein intake may be significant contributing factors. The most recent findings regarding the role of nutritional intake on protein metabolism in the elderly will be reviewed. Specifically, aging is associated with changes in the muscle protein metabolism response to a meal, likely due to alterations in the response to endogenous hormones. Nonetheless, the older muscle is still able to respond to amino acids, mainly the essential and BCAAs, which have been shown to acutely stimulate muscle protein synthesis in older individuals. It is likely that this stimulatory effect of essential and BCAA is due to the direct effect of leucine on the initiation of mRNA translation, which is still present in older age, although it appears to be attenuated in aged animals. Recent data suggest that excess leucine may be able to overcome this age-related resistance of muscle proteins to leucine. For this reason, long-term essential amino acid supplementation may be a useful tool for the prevention and treatment of sarcopenia, particularly if excess leucine is provided in the supplement.


Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble.
The 64-kDa pancreatic beta-cell autoantigen, which is a target of autoantibodies associated with early as well as progressive stages of beta-cell destruction, resulting in insulin-dependent diabetes (IDDM) in humans, has been identified as the gamma-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase. We have identified two autoantigenic forms of this protein in rat pancreatic beta-cells, a Mr 65,000 (GAD65) hydrophilic and soluble form of pI 6.9-7.1 and a Mr 64,000 (GAD64) component of pI 6.7. GAD64 is more abundant than GAD65 and has three distinct forms with regard to cellular compartment and hydrophobicity. A major portion of GAD64 is hydrophobic and firmly membrane-anchored and can only be released from membrane fractions by detergent. A second portion is hydrophobic but soluble or of a low membrane avidity, and a third minor portion is soluble and hydrophilic. All the GAD64 forms have identical pI and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results of pulse-chase labeling with [35S]methionine are consistent with GAD64 being synthesized as a soluble protein that is processed into a firmly membrane-anchored form in a process which involves increases in hydrophobicity but no detectable changes in size or charge. All the GAD64 forms can be resolved into two isoforms, alpha and beta, which differ by approximately 1 kDa in mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis but are identical with regard to all other parameters analyzed in this study. GAD65 has a shorter half-life than the GAD64 forms, remains hydrophilic and soluble, and does not resolve into isomers. Comparative analysis of the brain and beta-cell forms of GAD show that GAD65 and GAD64 in pancreatic beta-cells correspond to the larger and smaller forms of GAD in brain, respectively. The expression of different forms and the flexibility in subcellular localization of the GAD autoantigen in beta-cells may have implications for both its function and autoantigenicity.


Men's Understanding of and Experiences During the Postcircumcision Abstinence Period: Results From a Field Study of ShangRing Circumcision During Routine Clinical Services in Kenya and Zambia.
Men's understanding of counseling messages after voluntary medical male circumcision (VMMC) plays an important role in whether they follow them. Data on triggers for early resumption of sex may be useful as scale-up of VMMC for HIV prevention continues in sub-Saharan Africa. Data on understanding of post-VMMC abstinence recommendations, resumption of sex, condom use, and triggers for resuming sex were collected from participants during a follow-up interview 35-42 days after ShangRing circumcision in Kenya and Zambia. Of 1149 men who had ShangRing circumcision, 1096 (95.4%) completed follow-up. Nearly all (99.2%) reported being counseled to abstain from sex post-VMMC; among those, most (92.2%) recalled the recommended abstinence period was 6 weeks. Most men (94.1%) reported that the counselor gave reasons for post-VMMC abstinence and recalled appropriate reasons. Few (13.4%) men reported resuming sex at 35-42 days' follow-up. Among those, 54.8% reported never using a condom post-VMMC. Younger participants (odds ratio 0.3, 95% confidence interval: 0.2 to 0.5, P < 0.0001) and those reporting at least some condom use at baseline (odds ratio 0.5, 95% confidence interval: 0.3 to 0.7, P = 0.0003) were less likely to report resuming sex. Among men who reported some condom use, most (71.5%) said condoms were much easier or easier to use after circumcision. Men reported various reasons for early resumption of sex, primarily strong sexual desire (76.4%). Most men reported awareness of and adherence to the counseling recommendations for post-VMMC abstinence. A minority reported early resumption of sex, and, among those, condom use was low. Results could be used to improve post-VMMC counseling.


Missouri Mothers and Their Children: A Family Study of the Effects of Genetics and the Prenatal Environment.
The Missouri Mothers and Their Children Study (MO-MATCH) was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record (BR) database. Interview and lab-based data were obtained from: (1) mothers of Missouri-born children (born 1998-2005), who smoked during one pregnancy but not during another pregnancy; (2) biological fathers when available; and (3) the children (i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP). This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre, peri, and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance used initiation.


A novel steroidal saponin glycoside from Fagonia indica induces cell-selective apoptosis or necrosis in cancer cells.
Fagonia indica is a small spiny shrub of great ethnopharmacological importance in folk medicine. The aqueous decoction of aerial parts is a popular remedy against various skin lesions, including cancer. We used a biological activity-guided fractionation approach to isolate the most potent fraction of the crude extract on three cancer cell lines: MCF-7 oestrogen-dependent breast cancer, MDA-MB-468 oestrogen-independent breast cancer, and Caco-2 colon cancer cells. A series of chromatographic and spectroscopic procedures were utilised on the EtOAc fraction, which resulted in the isolation of a new steroidal saponin glycoside. The cytotoxic activity of the saponin glycoside was determined in cancer cells using the MTT and neutral red uptake assays. After 24h treatment, the observed IC(50) values of the saponin glycoside were 12.5 μM on MDA-MB-468 and Caco-2 cells, but 100 μM on MCF-7 cells. Several lines of evidence: PARP cleavage, caspase-3 cleavage, DNA ladder assays, and reversal of growth inhibition with the pan-caspase inhibitor Z-VAD-fmk, suggested stimulation of apoptosis in MDA-MB-468 and Caco-2 cells, but not in MCF-7 cells, which do not express caspase-3. The haemolytic activity of the saponin glycoside was confirmed in sheep red blood cells, with cell lysis observed at >100 μM, suggesting that, at this concentration, the saponin glycoside caused necrosis through cell lysis in MCF-7 cells. Using the DNA ladder assay, the saponin glycoside (12.5 μM) was not toxic to HUVEC (human umbilical vein endothelial cells) or U937 cells, indicating some selectivity between malignant and normal cells. We conclude that the steroidal saponin glycoside isolated from F. indica is able to induce apoptosis or necrosis in cancer cells depending on the cell type.


Infection, reinfection, and vaccination under suboptimal immune protection: epidemiological perspectives.
The SIR (susceptible-infectious-resistant) and SIS (susceptible-infectious-susceptible) frameworks for infectious disease have been extensively studied and successfully applied. They implicitly assume the upper and lower limits of the range of possibilities for host immune response. However, the majority of infections do not fall into either of these extreme categories. We combine two general avenues that straddle this range: temporary immune protection (immunity wanes over time since infection), and partial immune protection (immunity is not fully protective but reduces the risk of reinfection). We present a systematic analysis of the dynamics and equilibrium properties of these models in comparison to SIR and SIS, and analyse the outcome of vaccination programmes. We describe how the waning of immunity shortens inter-epidemic periods, and poses major difficulties to disease eradication. We identify a "reinfection threshold" in transmission when partial immunity is included. Below the reinfection threshold primary infection dominates, levels of infection are low, and vaccination is highly effective (approximately an SIR model). Above the reinfection threshold reinfection dominates, levels of infection are high, and vaccination fails to protect (approximately an SIS situation). This association between high prevalence of infection and vaccine failure emphasizes the problems of controlling recurrent infections in high-burden regions. However, vaccines that induce a better protection than natural infection have the potential to increase the reinfection threshold, and therefore constitute interventions with a surprisingly high capacity to reduce infection where reduction is most needed.


Correlation of pressure measurements with angiographic characteristics predisposing to hemorrhage and steal in cerebral arteriovenous malformations.
To determine whether there is a physiologic explanation for the predisposition of patients with certain angiographic characteristics to symptoms of hemorrhage and steal. Superselective transcatheter feeding arterial pressure and mean arterial pressure measurements were obtained before embolotherapy in 32 patients with cerebral arteriovenous malformations. Pressures were correlated with previously described angioarchitectural characteristics predisposing to hemorrhage and steal. These included size of the arteriovenous malformation, feeding artery length, venous drainage pattern, and angiomatous change. The feeding arterial pressure and feeding arterial pressure/mean arterial pressure ratios were significantly decreased in patients with angiomatous change. Feeding arterial pressure and feeding arterial pressure/mean arterial pressure ratios progressively decreased as lesions went from peripheral, to mixed, to central venous drainage. A trend for lower feeding arterial pressure was also demonstrated with greater feeding pedicle length. A statistically significant correlation could not be demonstrated between feeding arterial pressure or feeding arterial pressure/mean arterial pressure ratios and size of the arteriovenous malformation, hemorrhage, or symptoms of steal. Feeding arterial pressure measurements help provide a physiologic basis for the relationship between certain angiographic characteristics and hemorrhage and steal symptoms in patients with arteriovenous malformation.


Biocontrol Potential of Steinernema thermophilum and Its Symbiont Xenorhabdus indica Against Lepidopteran Pests: Virulence to Egg and Larval Stages.
Under laboratory conditions, the biocontrol potential of Steinernema thermophilum was tested against eggs and larval stages of two important lepidopteran insect pests, Helicoverpa armigera and Spodoptera litura (polyphagous pests), as well as Galleria mellonella (used as a model host). In terms of host susceptibility of lepidopteran larvae to S. thermophilum, based on the LC50 36 hr after treatment, G. mellonella (LC50 = 16.28 IJ/larva) was found to be more susceptible than S. litura (LC50 = 85 IJ/larva), whereas neither host was found to be significantly different from H. armigera (LC50 = 54.68 IJ/larva). In addition to virulence to the larval stages, ovicidal activity up to 84% was observed at 200 IJ/50 and 100 eggs of H. armigera and S. litura, respectively. To our knowledge this is the first report of entomopathogenic nematode pathogenicity to lepidopteran eggs. Production of infective juvenile (IJ) nematodes/insect larva was also measured and found to be positively correlated with rate of IJ for H. armigera (r = 0.990), S. litura (r = 0.892), as well as G. mellonella (r = 0.834). Both Phase I and Phase II of symbiotic bacteria Xenorhabdus indica were tested separately against neonates of H. armigera and S. litura by feeding assays and found to be virulent to the target pests; phase variation did not affect the level of virulence. Thus S. thermophilum as well as the nematode's symbiotic bacteria applied separately have the potential to be developed as biocontrol agents for key lepidopteran pests.


Personal exposure monitoring of PM2.5 in indoor and outdoor microenvironments.
Adverse health effects from exposure to air pollution are a global challenge and of widespread concern. Recent high ambient concentration episodes of air pollutants in European cities highlighted the dynamic nature of human exposure and the gaps in data and knowledge about exposure patterns. In order to support health impact assessment it is essential to develop a better understanding of individual exposure pathways in people's everyday lives by taking account of all environments in which people spend time. Here we describe the development, validation and results of an exposure method applied in a study conducted in Scotland. A low-cost particle counter based on light-scattering technology - the Dylos 1700 was used. Its performance was validated in comparison with equivalent instruments (TEOM-FDMS) at two national monitoring network sites (R(2)=0.9 at a rural background site, R(2)=0.7 at an urban background site). This validation also provided two functions to convert measured PNCs into calculated particle mass concentrations for direct comparison of concentrations with equivalent monitoring instruments and air quality limit values. This study also used contextual and time-based activity data to define six microenvironments (MEs) to assess everyday exposure of individuals to short-term PM2.5 concentrations. The Dylos was combined with a GPS receiver to track movement and exposure of individuals across the MEs. Seventeen volunteers collected 35 profiles. Profiles may have a different overall duration and structure with respect to times spent in different MEs and activities undertaken. Results indicate that due to the substantial variability across and between MEs, it is essential to measure near-complete exposure pathways to allow for a comprehensive assessment of the exposure risk a person encounters on a daily basis. Taking into account the information gained through personal exposure measurements, this work demonstrates the added value of data generated by the application of low-cost monitors.


Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.
Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.


The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation.
Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 +/- 81.1 m/dl; mean +/- SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P less than 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.


Success and failure in integrated models of nursing for long term conditions: multiple case studies of whole systems.
Current projections indicate that the UK faces a 252% increase in people aged over 65 with one or more long term conditions (LTC) by 2050. Nurses, managing their own caseloads and clinics, working across sectors and organisational boundaries and as part of a wider multi-disciplinary team, are frequently seen as key to managing this growing demand. However, the evidence base informing the nursing role in managing LTC, the most effective configuration of the multi-disciplinary team and the policy evidence relating to the infrastructure required to support cross organisational working, remains weak. To explore, identify and characterise the origins, processes and outcomes of effective chronic disease management models and the nursing contributions to such models. Case study whole systems analysis using qualitative interview methods. Two community matron services, two primary care (GP) practice nursing services, two hospital based specialist nursing services were purposefully sampled from across England and Wales. Selection criteria were derived using a consensus conference. The nurses in the service, all patients and carers on the caseload, members of the multi-disciplinary team and stakeholders were invited to participate. Semi-structured interviews with all participants, thematic analysis within a whole system framework. The study found high levels of clinical nursing expertise which in the case of the community matrons was meeting the aim of reducing hospital admissions. Both the primary care and hospital nurse specialist indicate similar levels of clinical expertise which was highly valued by medical colleagues and patients. Patients continued to experience fragmented care determined by diagnostic categories rather than patient need and by the specific remit of the clinic or service the patient was using. Patient data systems are still organised around the impact on services and prevalence of disease at an individual level and not around the patient experience of disease. Nurses are making a major contribution to meeting the policy objectives for long term conditions. Primary care nurses and hospital nurse specialists do broadly similar roles. The scope of the nursing roles and services studied were idiosyncratic, opportunistic and reactive, rather than planned and commissioned on an analysis of local population need.


[Obesity in children].
Obesity during childhood and adolescence is an increasingly common complaint in our daily clinical practice. The increase in its prevalence makes paediatrician worry about this disease, which is now considered an epidemic by the World Health Organisation. Obesity is a complex disease. Its aetiology is not yet clear, due to the multiple factors involved: environment, genetics, behaviour, life style, neuroendocrinology and metabolism. Persistent obesity increases the risk of suffering from diabetes, cardiovascular disease, hypertension, and gallbladder disease. The treatment of obesity is problematic and there are few patients who persist on a long term weight reduction programme. A multidisciplinary approach is therefore required. Paediatricians, dieticians, nurses, psychologists and psychiatrist should intervene in the treatment programme. Dietary changes must combine a decrease in energy intake and an increase in energy expenditure, inculcating both healthy eating habits and lifestyle without interfering in the child's growth and development.


Differential IL-1β secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability.
Monocytes play a central role in regulating inflammation in response to infection or injury, and during auto-inflammatory diseases. Human blood contains classical, intermediate and non-classical monocyte subsets that each express characteristic patterns of cell surface CD16 and CD14; each subset also has specific functional properties, but the mechanisms underlying many of their distinctive features are undefined. Of particular interest is how monocyte subsets regulate secretion of the apical pro-inflammatory cytokine IL-1β, which is central to the initiation of immune responses but is also implicated in the pathology of various auto-immune/auto-inflammatory conditions. Here we show that primary human non-classical monocytes, exposed to LPS or LPS + BzATP (3'-O-(4-benzoyl)benzyl-ATP, a P2X7R agonist), produce approx. 80% less IL-1β than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1β instead arose from 50% increased IL-1β mRNA decay rates, mediated by Hsp27. These findings identify the Hsp27 pathway as a novel therapeutic target for the management of conditions featuring dysregulated IL-1β production, and represent an advancement in understanding of both physiological inflammatory responses and the pathogenesis of inflammatory diseases involving monocyte-derived IL-1β.


If looks could heal: Child health and paternal investment.
Data from the first two waves of the Fragile Family and Child Wellbeing study indicate that infants who look like their father at birth are healthier one year later. The reason is such father-child resemblance induces a father to spend more time engaged in positive parenting. An extra day (per month) of time-investment by a typical visiting father enhances child health by just over 10% of a standard deviation. This estimate is not biased by the effect of child health on father-involvement or omitted maternal ability, thereby eliminating endogeneity biases that plague existing studies. The result has implications regarding the role of a father's time in enhancing child health, especially in fragile families.


First Report of Sclerotinia Blight Caused by Sclerotinia sclerotiorum on Spearmint in Northern Italy.
Spearmint (Mentha spicata L.) is an aromatic plant belonging to the family Lamiaceae, grown as well as an ornamental potted plant. During the beginning of 2013, extensive wilting was observed on 4-month-old potted plants of M. spicata 'Moroccan' grown in a commercial, unheated, plastic house located near Albenga (Savona, northern Italy). Initial symptoms included stem necrosis and darkening and withering of leaves. Wilting of the plant occurred 2 to 4 days after the appearance of the initial symptoms. Infected plants were characterized by the presence of cottony soft rot. In the presence of high relative humidity, lesions became covered with a whitish mycelium and irregular, dark gray sclerotia (2.0 to 9.0 × 1.8 to 4.0, average 4.0 × 2.6 mm) were produced on the mycelium. Diseased tissue was surface sterilized for 1 min in 1% NaOCl and plated on potato dextrose agar (PDA) amended with 100 mg/l streptomycin sulfate. White colonies developed from infected stem pieces and produced sclerotia, mainly at the peripheries of the plates, measuring 2.0 to 8.0 × 2.0 to 6.0 (average 4.4 × 3.1) mm. The internal transcribed spacer (ITS) region of rDNA was amplified using the primers ITS1F/ITS4 and sequenced. BLAST analysis (1) of the 514-bp segment showed a 99% homology with the sequence of Sclerotinia sclerotiorum (JN012605). The nucleotide sequence has been assigned the GenBank Accession KC848769. The morphological and molecular identification permitted to identify as S. sclerotiorum (Lib.) de Bary (2) the causal agent of the disease observed on M. spicata. Pathogenicity of one isolate obtained from infected plants was confirmed by inoculating three 7-month-old plants cv. Moroccan transplanted in 1 liter pots in a glasshouse in a sphagnum peat/pomix/pine bark/clay (50:20:20:10) mix. Each plant was inoculated by placing 4 g of sterile wheat kernels infested with mycelium and sclerotia in the soil and around the collar. Three non-inoculated plants served as controls. Plants were maintained in a growth chamber at 24 ± 1°C and relative humidity >90%. The inoculation trial was carried out twice. All inoculated plants developed the symptoms, consisting of stem necrosis, 5 days after soil infestation, followed by leaf yellowing. White cottony mycelium and dark sclerotia developed on stems and at the base of all inoculated plants. Eventually, infected plants wilted. Control plants remained symptomless. S. sclerotiorum was reisolated from the stems of inoculated plants. To our knowledge, this is the first report of S. sclerotiorum on M. spicata in Italy as well as worldwide. The disease has been previously reported on M. piperita in the United States (4) and on M. arvensis in India (3). The economic importance of this disease in Italy is at present limited. References: (1) S. F. Altschul et al. Nucleic Acids Res. 25:3389, 1997. (2) N. F. Buchwald. Kongl. Veterisk Landb. Aarssk. 75, 1949. (3) K. Perveen et al. Indian Phytopathol. 62:310, 2009. (4) C. B. Skotland and J. D. Menzies. Plant Dis. Rep. 41:493, 1957.


Photomodulation of the nucleating activity of a photocleavable crosslinked actin dimer.
The ability to generate substrate concentration jumps through photo-deprotection of amine, carboxyl and phosphate groups has been an important development for investigations of protein activity in complex systems. To broaden the versatility and applications of photo-deprotection techniques for the photomodulation of protein activity we describe the synthesis and characterisation of a reagent for generating free thiol from thioether groups and a related photocleavable, heterobifunctional crosslinking reagent. Chemical and spectroscopic studies of a model thiol protected derivative were used to show some features of thiol group photodeprotection. To demonstrate how the photocleavable crosslinking reagent may be used to modulate the activity of proteins we investigated the effect of light on the nucleating activity of crosslinked actin dimer; thus following near-ultraviolet irradiation of the actin dimer the crosslink was cleaved, presumeably at the thioether bond, resulting in the concomitant dissociation of dimer, loss of nucleating activity and creation of a concentration jump of polymerisable G-actin monomer. On the basis of this initial study we discuss applications and limitations of these reagents for the photomodulation of protein activity in vitro and in vivo.


Molecular insights into the selective action of a magnetically removable complexone-grafted adsorbent.
The binding and release of trivalent rare earth element (REE) cations (Dy(3+), Nd(3+) and La(3+)) from solutions by a new fully characterized magnetic nano adsorbent material, consisting of iminodiacetic acid ligand (H2IDA) grafted onto SiO2 covered γ-Fe2O3 nanoparticles, was investigated. The nano adsorbent revealed a slightly higher capacity towards heavier REE and appreciable selectivity, especially on desorption. It was found that the composition of the surface complex was RE(3+) : L = 1 : 1. The complexation of the molecular H2IDA with RE(3+) in this ratio under non-basic conditions was therefore investigated by X-ray crystallography to produce relevant molecular models. Unexpectedly big differences in coordination numbers and binding mode of IDA along with distinct analogies in packing of the ligand molecules in the obtained 2D-coordination polymer structures provided valuable insights into possible reasons for the observed selectivity.


Liver volume in the cirrhotic patient: does size matter?
While it is established that cirrhosis results in a decrease in liver volume (LV), whether LV itself predicts patient survival is unknown. We hypothesize that estimated LV is an important prognostic indicator in patients with cirrhosis. Data was gathered retrospectively from consecutive patients evaluated for a liver transplant from January 2001 to June 2006. Of 500 patients identified, 323 patients met both inclusion and exclusion criteria. LV per ideal body weight (IBW) was used to correct for body size, and LV/IBW was stratified by median split for survival analyses. Patients were classified into one of three clinical groups: hepatocellular disease (n = 229), cholestatic disease (n = 56), and miscellaneous (n = 38). One of three possible clinical outcomes (survival, liver transplantation, or death) was recorded during the 5-year follow-up, the latter two grouped together as "transplant/death." Transplant/death occurred in 283 (88 %) subjects. Overall, there was a significant increase in transplant/death in those with lower LV/IBW (χ(2) = 5.27, p = 0.022). When considering the subset with hepatocellular disease, lower LV/IBW was a robust predictor of transplant/death (χ(2) = 9.62, p = 0.002). In multivariate analyses, the LV/IBW trended toward predicting transplant/death (ExpB = 0.943, p = 0.053) independent of Model for End stage Liver Disease (MELD) (ExpB = 1.13, p = 0.001). LV has important predictive value in patients with cirrhosis from hepatocellular disease. This observation appears to be independent of MELD, suggesting LV may impart important prognostic information that is not captured by the MELD score alone. Thus, LV may serve as an important adjunct to the MELD score in patients with hepatocellular disease.


Asthma and adherence to inhaled corticosteroids: current status and future perspectives.
Inhaled corticosteroids (ICS) are the cornerstone of maintenance asthma therapy. However, in spite of this, adherence to ICS remains low. The aim of this systematic literature review was to provide an overview of the current knowledge of adherence to ICS, effects of poor adherence, and means to improve adherence. A total of 19 studies met the inclusion criteria: 9 focusing on the level of adherence, 6 focusing on effects of poor adherence, and 7 focusing on interventions to improve adherence. Three of the studies focused on more than one of these end points. The mean level of adherence to ICS was found to be between 22 and 63%, with improvement up to and after an exacerbation. Poor adherence was associated with youth, being African-American, having mild asthma, < 12 y of formal education, and poor communication with the health-care provider, whereas improved adherence was associated with being prescribed fixed-combination therapy (ICS and long-acting β2 agonists). Good adherence was associated with higher FEV1, a lower percentage of eosinophils in sputum, reduction in hospitalizations, less use of oral corticosteroids, and lower mortality rate. Overall, 24% of exacerbations and 60% of asthma-related hospitalizations could be attributed to poor adherence. Most studies have reported an increase in adherence following focused interventions, followed by an improvement in quality of life, symptoms, FEV1, and oral corticosteroid use. However, 2 studies found no difference in health-care utilization, one observed no effect on symptoms, and one observed more symptoms in subjects in the intervention group compared with the control group. Good adherence to ICS in asthma improves outcome but remains low. Interventions to improve adherence show varying results, with most studies reporting an increase in adherence but unfortunately not necessarily an improvement in outcome. Even following successful interventions, adherence remains low. Further research is needed to explore barriers to adherence and interventions for improvement.


An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost.
Lung cancer screening is not established as a public health practice, yet the results of a recent large randomized controlled trial showed that screening with low-dose spiral computed tomography reduces lung cancer mortality. Using actuarial models, this study estimated the costs and benefits of annual lung cancer screening offered as a commercial insurance benefit in the high-risk US population ages 50-64. Assuming current commercial reimbursement rates for treatment, we found that screening would cost about $1 per insured member per month in 2012 dollars. The cost per life-year saved would be below $19,000, an amount that compares favorably with screening for cervical, breast, and colorectal cancers. Our results suggest that commercial insurers should consider lung cancer screening of high-risk individuals to be high-value coverage and provide it as a benefit to people who are at least fifty years old and have a smoking history of thirty pack-years or more. We also believe that payers and patients should demand screening from high-quality, low-cost providers, thus helping set an example of efficient system innovation.


C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner.
Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.


Co-bedding in neonatal nursery for promoting growth and neurodevelopment in stable preterm twins.
The increased birth rate of twins during recent decades and the improved prognosis of preterm infants have resulted in the need to explore measures that could optimize their growth and neurodevelopmental outcomes. It has been postulated that co-bedding simulates twins' intrauterine experiences in which co-regulatory behaviors between them are observed. These behaviors are proposed to benefit twins by reducing their stress, which may promote growth and development. However, in practice, uncertainty surrounds the benefit-risk profile of co-bedding. We aimed to assess the effectiveness of co-bedding compared with separate (individual) care for stable preterm twins in the neonatal nursery in promoting growth and neurodevelopment and reducing short- and long-term morbidities, and to determine whether co-bedding is associated with significant adverse effects.As secondary objectives, we sought to evaluate effects of co-bedding via the following subgroup analyses: twin pairs with different weight ranges (very low birth weight [VLBW] < 1500 grams vs non-VLBW), twins with versus without significant growth discordance at birth, preterm versus borderline preterm twins, twins co-bedded in incubator versus cot at study entry, and twins randomized by twin pair versus neonatal unit. We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG). We used keywords and medical subject headings (MeSH) to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE (via PubMed), EMBASE (hosted by EBSCOHOST), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and references cited in our short-listed articles, up to February 29, 2016. We included randomized controlled trials with randomization by twin pair and/or by neonatal unit. We excluded cross-over studies. We extracted data using standard methods of the CNRG. Two review authors independently assessed the relevance and risk of bias of retrieved records. We contacted the authors of included studies to request important information missing from their published papers. We expressed our results using risk ratios (RRs) and mean differences (MDs) when appropriate, along with 95% confidence intervals (95% CIs). We adjusted the unit of analysis from individual infants to twin pairs by averaging measurements for each twin pair (continuous outcomes) or by counting outcomes as positive if developed by either twin (dichotomous outcomes). Six studies met the inclusion criteria; however, only five studies provided data for analysis. Four of the six included studies were small and had significant limitations in design. As each study reported outcomes differently, data for most outcomes were effectively contributed by a single study. Study authors reported no differences between co-bedded twins and twins receiving separate care in terms of rate of weight gain (MD 0.20 grams/kg/d, 95% CI -1.60 to 2.00; one study; 18 pairs of twins; evidence of low quality); apnea, bradycardia, and desaturation (A/B/D) episodes (RR 0.85, 95% CI 0.18 to 4.05; one study; 62 pairs of twins; evidence of low quality); episodes in co-regulated states (MD 0.96, 95% CI -3.44 to 5.36; one study; three pairs of twins; evidence of very low quality); suspected or proven infection (RR 0.84, 95% CI 0.30 to 2.31; three studies; 65 pairs of twins; evidence of very low quality); length of hospital stay (MD -4.90 days, 95% CI -35.23 to 25.43; one study; three pairs of twins; evidence of very low quality); and parental satisfaction measured on a scale of 0 to 55 (MD -0.38, 95% CI -4.49 to 3.73; one study; nine pairs of twins; evidence of moderate quality). Although co-bedded twins appeared to have lower pain scores 30 seconds after heel lance on a scale of 0 to 21 (MD -0.96, 95% CI -1.68 to -0.23; two studies; 117 pairs of twins; I(2) = 75%; evidence of low quality), they had higher pain scores 90 seconds after the procedure (MD 1.00, 95% CI 0.14 to 1.86; one study; 62 pairs of twins). Substantial heterogeneity in the outcome of infant pain response after heel prick at 30 seconds post procedure and conflicting results at 30 and 90 seconds post procedure precluded clear conclusions. Evidence on the benefits and harms of co-bedding for stable preterm twins was insufficient to permit recommendations for practice. Future studies must be adequately powered to detect clinically important differences in growth and neurodevelopment. Researchers should assess harms such as infection, along with medication errors and caregiver satisfaction.


High temporal but low spatial heterogeneity of bacterioplankton in the Chesapeake Bay.
Compared to freshwater and the open ocean, less is known about bacterioplankton community structure and spatiotemporal dynamics in estuaries, particularly those with long residence times. The Chesapeake Bay is the largest estuary in the United States, but despite its ecological and economic significance, little is known about its microbial community composition. A rapid screening approach, ITS (internal transcribed spacer)-LH (length heterogeneity)-PCR, was used to screen six rRNA operon (16S rRNA-ITS-23S rRNA) clone libraries constructed from bacterioplankton collected in three distinct regions of the Chesapeake Bay over two seasons. The natural length variation of the 16S-23S rRNA gene ITS region, as well as the presence and location of tRNA-alanine coding regions within the ITS, was determined for 576 clones. Clones representing unique ITS-LH-PCR sizes were sequenced and identified. Dramatic shifts in bacterial composition (changes within subgroups or clades) were observed for the Alphaproteobacteria (Roseobacter clade, SAR11), Cyanobacteria (Synechococcus), and Actinobacteria, suggesting strong seasonal variation within these taxonomic groups. Despite large gradients in salinity and phytoplankton parameters, a remarkably homogeneous bacterioplankton community was observed in the bay in each season. Stronger seasonal, rather than spatial, variation of the bacterioplankton population was also supported by denaturing gradient gel electrophoresis and LH-PCR analyses, indicating that environmental parameters with stronger seasonal, rather than regional, dynamics, such as temperature, might determine bacterioplankton community composition in the Chesapeake Bay.


Protein, Calcium, Vitamin D Intake and 25(OH)D Status in Normal Weight, Overweight, and Obese Older Adults: A Systematic Review and Meta-Analysis.
The aging process is often accompanied by increase in body weight. Older adults with overweight or obesity might have an overconsumption in energy that is accompanied by inadequate intake of protein, vitamin D, and calcium. It is unclear if intake of protein and vitamin D and calcium is sufficient in older adults with overweight/obesity, and whether it differs from older adults with normal weight, since a recent overview of the literature review is lacking. Therefore, we systematically analyzed the current evidence on differences in nutrient intake/status of protein, vitamin D and calcium between older adults with different body mass index (BMI) categories. Randomized controlled trials and prospective cohort studies were identified from PubMed and EMBASE. Studies reporting nutrient intake/status in older adults aged ≥50 years with overweight/obesity and studies comparing between overweight/obesity and normal weight were included. Nutrient intake/status baseline values were reviewed and when possible calculated for one BMI category (single-group meta-analysis), or compared between BMI categories (meta-analysis). Nutrient intake/status was compared with international recommendations. Mean protein (N = 8) and calcium intake (N = 5) was 0.98 gram/kilogram body weight/day (g/kg/d) [95% Confidence Interval (CI) 0.89-1.08] and 965 mg [95% CI: 704-1225] in overweight/obese. Vitamin D intake was insufficient in all BMI categories (N = 5). The pooled mean for vitamin D intake was 6 ug [95% CI 4-9]. For 25(OH)D, the pooled mean was 54 nmol/L [95% CI 45-62], 52 nmol/L [95% CI 46-58], and 48 nmol/l [95% CI 33-62] in normal (N = 7), combined overweight and obese (N = 12), and obese older adults (N = 4), respectively. In conclusion, older adults with overweight and obesity have a borderline sufficient protein and sufficient calcium intake, but insufficient vitamin D intake. The 25(OH)D concentration is deficient for the obese older adults.


Is Ankyrin a genetic risk factor for psychiatric phenotypes?
Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.


Safety and efficacy of a new tourniquet system.
In upper limb surgery, the pneumatic tourniquet is an essential tool to provide a clean, bloodless surgical field, improving visualization of anatomical structures and preventing iatrogenic failure. Optimal inflation pressure to accomplish these objects without injuring normal tissue and inducing complications is not yet established. Use of the minimum tourniquet pressure necessary to produce a bloodless surgical field is preferable in order to prevent injury to normal tissue. Various methods have been implemented in an effort to lower effective cuff pressure. The purpose of this study is to report clinical experience with a new tourniquet system in which pressure is synchronized with systolic blood pressure (SBP) using a vital information monitor. We routinely used the tourniquet system in 120 consecutive upper limb surgeries performed under general anaesthesia in our operating room instead of our clinic. Cuff pressure was automatically regulated to additional 100 mmHg based on the SBP and was renewed every 2.5 minutes intervals. An excellent bloodless field was obtained in 119 cases, with the exception of one case of a 44-year-old woman who underwent internal screw fixation of metacarpal fracture. No complications, such as compartment syndrome, deep vein disorder, skin disorder, paresis, or nerve damage, occurred during or after surgery. This new tourniquet system, synchronized with SBP, can be varied to correspond with sharp rises or drops in SBP to supply adequate pressure. The system reduces labor needed to deflate and re-inflate to achieve different pressures. It also seemed to contribute to the safety in upper limb surgery, in spite of rare unexpected oozing mid-surgery, by reducing tissue pressure.


Blockade of glioma proliferation through allosteric inhibition of JAK2.
The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)-mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neurosphere cultures, but the drug only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere with either ligand or adenosine 5'-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating that this allosteric JAK2 inhibitor may be an effective clinical strategy.


A combined chemical imaging approach using (MC) LA-ICP-MS and NIR-HSI to evaluate the diagenetic status of bone material for Sr isotope analysis.
This paper presents a combination of elemental and isotopic spatial distribution imaging with near-infrared hyperspectral imaging (NIR-HSI) to evaluate the diagenetic status of skeletal remains. The aim is to assess how areas with biogenic n(87Sr)/n(86Sr) isotope-amount ratios may be identified in bone material, an important recorder complementary to teeth. Elemental (C, P, Ca, Sr) and isotopic (n(87Sr)/n(86Sr)) imaging were accomplished via laser ablation (LA) coupled in a split stream to a quadrupole inductively coupled plasma mass spectrometer (ICP-QMS) and a multicollector inductively coupled plasma mass spectrometer (MC ICP-MS) (abbreviation for the combined method LASS ICP-QMS/MC ICP-MS). Biogenic areas on the bone cross section, which remained unaltered by diagenetic processes, were localized using chemical indicators (I(C)/I(Ca) and I(C) × 10/I(P) intensity ratios) and NIR-HSI at a wavelength of 1410 nm to identify preserved collagen. The n(87Sr)/n(86Sr) isotope signature analyzed in these areas was in agreement with the biogenic bulk signal revealed by solubility profiling used as an independent method for validation. Elevated C intensities in the outer rim of the bone, caused by either precipitated secondary minerals or adsorbed humic materials, could be identified as indication for diagenetic alteration. These areas also show a different n(87Sr)/n(86Sr) isotopic composition. Therefore, the combination of NIR-HSI and LASS ICP-QMS/MC ICP-MS allows for the determination of preserved biogenic n(87Sr)/n(86Sr) isotope-amount ratios, if the original biogenic material has not been entirely replaced by diagenetic material. Graphical abstract .


The SOFIA pilot trial: a cluster-randomized trial of coordinated, co-produced care to reduce mortality and improve quality of life in people with severe mental illness in the general practice setting.
People with severe mental illness (SMI) have an increased risk of premature mortality, predominantly due to somatic health conditions. Evidence indicates that primary and tertiary prevention and improved treatment of somatic conditions in patients with SMI could reduce this excess mortality. This paper reports a protocol designed to evaluate the feasibility of a coordinated co-produced care program (SOFIA model, a Danish acronym for Severe Mental Illness and Physical Health in General Practice) in the general practice setting to reduce mortality and improve quality of life in patients with severe mental illness. The SOFIA pilot trial is designed as a cluster randomized controlled trial targeting general practices in two regions in Denmark. We aim to include 12 practices, each of which is instructed to recruit up to 15 community-dwelling patients aged 18 and older with SMI. Practices will be randomized by a computer in a ratio of 2:1 to deliver a coordinated care program or usual care during a 6-month study period. A randomized algorithm is used to perform randomization. The coordinated care program includes educational training of general practitioners and their clinical staff educational training of general practitioners and their clinical staff, which covers clinical and diagnostic management and focus on patient-centered care of this patient group, after which general practitioners will provide a prolonged consultation focusing on individual needs and preferences of the patient with SMI and a follow-up plan if indicated. The outcomes will be parameters of the feasibility of the intervention and trial methods and will be assessed quantitatively and qualitatively. Assessments of the outcome parameters will be administered at baseline, throughout, and at end of the study period. If necessary the intervention will be revised based on results from this study. If delivery of the intervention, either in its current form or after revision, is considered feasible, a future, definitive trial to determine the effectiveness of the intervention in reducing mortality and improving quality of life in patients with SMI can take place. Successful implementation of the intervention would imply preliminary promise for addressing health inequities in patients with SMI. The trial was registered in Clinical Trials as of November 5, 2020, with registration number NCT04618250 . Protocol version: January 22, 2021; original version.


Expression of the Arf tumor suppressor gene is controlled by Tgfbeta2 during development.
The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by ;abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous (PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor beta2 (Tgfbeta2) might control Arf expression, as we show that mice lacking Tgfbeta2 have primary vitreous hyperplasia similar to Arf(-/-) mice. Consistent with a potential linear pathway, Tgfbeta2 induces Arf transcription and p19(Arf) expression in cultured mouse embryo fibroblasts (MEFs); and Tgfbeta2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by beta-galactosidase activity in Arf(lacZ/+) mice, we show that Tgfbeta2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgfbeta receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1beta. In summary, Tgfbeta2 and p19(Arf) act in a linear pathway during embryonic development. We present the first evidence that p19(Arf) expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.


Recipients of hip replacement for arthritis are less likely to be Hispanic, independent of access to health care and socioeconomic status.
To compare the proportion of Hispanics among recipients of hip replacements for primary articular disorders, recipients of knee replacements for the same reason, and persons hospitalized for other reasons. Twelve of the 17 accredited hospitals in Bexar County, Texas, in which hip or knee replacement surgery is performed permitted us to review their medical records. From 1993 through 1995, 3,100 elective, non-fracture-related, hip or knee replacements were performed. These individuals were matched by age, sex, hospital, and month of admission with 4,604 persons hospitalized for other reasons. Age, sex, ethnic background, type of medical insurance, median household income by zip code of residence, joint replaced, and surgical diagnosis were abstracted from the medical records. The validity of variables abstracted from the medical records was tested by comparison with self-report data in 115 patients interviewed prior to elective hip or knee replacement surgery. During the study period, 2,275 subjects had a total knee replacement and 825 had a total hip replacement. Recipients of hip replacements were significantly less likely to be Hispanic than were recipients of knee replacements (19.5% versus 29.9%; odds ratio [OR] 0.57, 95% confidence interval [95% CI] 0.46-0.71; P < or = 0.001) or persons hospitalized for other reasons (29.4% Hispanic; OR 0.67, 95% CI 0.55-0.81). The under-representation of Hispanics was more pronounced among persons undergoing hip replacement for osteoarthritis compared with recipients of knee replacements for the same disease (OR 0.48, 95% CI 0.37-0.62). This pattern persisted after adjusting for age, sex, type of medical insurance, and median household income by the zip code of residence. Concordance between medical records and self-report data on ethnic background was high (kappa = 0.93). Recipients of hip replacement are less likely to be Hispanic than are other hospitalized persons with a similar level of access to care. The reasons for this under-representation probably involve factors in addition to lack of access to health care and low socioeconomic status. Further research is needed to understand the nature of such factors.


"All air-plasma" terahertz spectroscopy.
We demonstrate terahertz wave generation and detection capabilities up to 6 THz without the need for solid state materials, biased electrodes, or forward propagating signal collection. An "all air-plasma" terahertz system is used to encode explosive material resonant signatures into the 357 nm nitrogen fluorescence line of a bichromatic field-induced laser plasma filament. These results show the practicability to extend these measurements to remote locations where terahertz pulse information is no longer limited by water vapor absorption, phonon resonance, or signal collection directionality.


Using an AMACR (P504S)/34betaE12/p63 cocktail for the detection of small focal prostate carcinoma in needle biopsy specimens.
We assessed the usefulness of immunohistochemical analysis with a 3-antibody cocktail (alpha-methylacyl coenzyme A racemase [AMACR, or P504S], 34betaE12, p63) and a double-chromogen reaction for detection of limited prostate cancer in 138 needle biopsy specimens, including 82 with small foci of prostatic adenocarcinoma and 56 benign prostates. When carcinoma was present, red cytoplasmic granular staining (AMACR) in the malignant glands and cells and dark brown nuclear (p63) and cytoplasmic (34betaE12) staining in basal cells of adjacent nonmalignant glands were found. Of 82 cases of small foci of prostatic adenocarcinoma, 78 (95%) expressed AMACR; all malignant glands were negative for basal cell staining. All benign glands adjacent to malignant glands were recognized easily by basal cell marker positivity and little or no AMACR expression. No benign glands were simultaneously positive for AMACR and negative for basal cell markers (specificity, 100%). There were no differences in intensity and numbers of positive glands with double-chromogen staining compared with using 1-color staining. Our results indicate that immunohistochemistry with a 3-antibody cocktail and double chromogen is a simple and easy assay that can be used as a routine test, which overcomes the problems of studying small lesions in prostate needle biopsies with multiple immunohistochemical stains.


Coronavirus induction of class I major histocompatibility complex expression in murine astrocytes is virus strain specific.
Neurotropic strains of mouse hepatitis viruses (MHV) such as MHV-A59 (A59) and MHV-4 (JHMV) cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. They are widely used as models of human demyelinating diseases such as multiple sclerosis (MS), in which immune mechanisms are thought to participate in the development of lesions in the central nervous system (CNS). The effects of MHV infection on target cell functions in the CNS are not well understood, but A59 has been shown to induce the expression of MHC class I molecules in glial cells after in vivo and in vitro infection. Changes in class I expression in infected cells may contribute to the immunopathogenesis of MHV infection in the CNS. In this communication, a large panel of MHV strains was tested for their ability to stimulate class I expression in primary astrocytes in vitro. The data show that the more hepatotropic strains, such as MHV-A59, MHV-1, MHV-2, MHV-3, MHV-D, MHV-K, and MHV-NuU, were potent inducers of class I expression in astrocytes during acute infection, measured by radioimmunoassay. The Kb molecule was preferentially expressed over Db. By contrast, JHMV and several viral strains derived from it did not stimulate the expression of class I molecules. Assays of virus infectivity indicated that the class I-inducing activity did not correlate with the ability of the individual viral strain to replicate in astrocytes. However, exposure of the viruses or the supernatants from infected astrocytes to ultraviolet light abolished the class I-inducing activity, indicating that infectious virus is required for class I expression. These data also suggest that class I expression was induced directly by virus infection, and not by the secretion of a soluble substance into the medium by infected astrocytes. Finally, analyses of A59/JHMV recombinant viral strains suggest that class I-inducing activity resides in one of the A59 structural genes.


Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin.
To investigate the possible association of the variants in the nucleotide binding fold regions of the sulfonylurea receptor 1 (SUR1) gene with gestational diabetes mellitus (GDM), type 2 diabetes, and altered insulin secretion in Finnish subjects. The nucleotide binding fold regions of the SUR1 gene were amplified with polymerase chain reaction and screened by the single-strand conformational polymorphism analysis in 42 subjects with GDM and 40 subjects with type 2 diabetes. Detected variants were further investigated in 377 normoglycemic subjects by restriction fragment-length polymorphism analysis. The effect of the variants of the SUR1 gene on first-phase insulin secretion was studied in 295 normoglycemic subjects. In subjects with GDM or type 2 diabetes, one amino acid change (S1369A), four silent substitutions (R1273R, L829L, T759T, and K649K), and three intron variants were identified in the nucleotide binding fold regions of the SUR1 gene. A tagGCC allele of exon 16 splice acceptor site was more frequent in subjects with GDM (0.55 allele frequency, n = 42) and type 2 diabetes (0.60, n = 40) than in normoglycemic subjects (0.43, n = 377) (P1 = 0.024 and P2 = 0.009, respectively). Similarly, an AGG allele of the R1273R polymorphism was more common in subjects with GDM (0.87) and type 2 diabetes (0.87) than in normoglycemic subjects (0.74) (P1 = 0.009 and P2 = 0.001, respectively). However, the S1369A, R1273R, and cagGCC-->tagGCC variants of the SUR1 gene were not associated with altered first-phase insulin secretion in 295 normoglycemic subjects. These results suggest that a functional variant that contributes to the risk of GDM and type 2 diabetes may locate close to the SUR1 gene.


Is Older Age a Real Adverse Prognostic Factor in Women With Early-Stage Endometrial Carcinoma? A Matched Analysis.
The aim of this study was to evaluate if older age alone negatively impacts survival endpoints in women with early-stage uterine endometrioid carcinoma (EC), or its reported prognostic impact is due to an interaction with other well-known adverse factors using matched-analysis methodology. We identified 1254 patients with International Federation of Gynecology and Obstetrics stage I-II EC who underwent hysterectomy at our institution. We created 2 matched groups based on International Federation of Gynecology and Obstetrics stage, tumor grade, lymph node dissection status, and the type of adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were calculated. A total 297 women 70 years or older were matched with 297 women younger than 70 years. The 2 groups were well balanced except for age and higher body mass index in younger patients. There were no significant difference between older and younger patients in regard to 5-year RFS (85% vs 87%; P = 0.52) or DSS (93% for both groups with P = 0.77). Five-year OS was shorter in older patients (76% vs 88% with P < 0.001). On multivariate analysis for RFS and DSS, high tumor grade and the presence of lymphovascular space invasion (LVSI) were the only 2 predictors of shorter RFS and DSS (P = 0.01 and P = 0.02, and P = 0.01 and P = 0.01, respectively). Tumor grade and LVSI also were predictors of shorter OS. Our study suggests that when older patients with EC are matched with younger patients based on tumor stage, grade, and adjuvant management the prognostic impact of old age disappears. High tumor grade and LVSI remained as independent predictors of survival endpoints.


How Mental Health Professionals Can Address Disparities in the Context of the COVID-19 Pandemic.
The Coronavirus 2019 (COVID-19) pandemic is an unparalleled crisis, yet also a unique opportunity for mental health professionals to address and prioritize mental and physical health disparities that disproportionately impact marginalized populations. Black, Indigenous, and People of Color (BIPOC) have long experienced structural racism and oppression, resulting in disproportionately high rates of trauma, poverty, and chronic diseases that span generations and are associated with increased COVID-19 morbidity and mortality rates. The current pandemic, with the potential of conferring new trauma exposure, interacts with and exacerbates existing disparities. To assist mental health professionals in offering more comprehensive services and programs for those who have minimal resources and the most profound barriers to care, four critical areas are highlighted as being historically problematic and essential to address: (a) recognizing psychology's role in institutionalizing disparities; (b) examining race/ethnicity as a critical variable; (c) proactively tackling growing mental health problems amidst the COVID-19 crisis; and (d) understanding the importance of incorporating historical trauma and discrimination in research and practice. Recommendations are provided to promote equity at the structural (e.g., nationwide, federal), professional (e.g., the mental health professions), and individual (e.g., practitioners, researchers) levels.


Evaluation of oral health status and influential factors in children with autism.
The aim of the present study was to comparatively analyze oral health status and influential factors in children with autism living in the Western Mediterranean Region of Turkey. This cross-sectional study was conducted in two steps: 1 - questionnaire and 2 - interview. This study was conducted at the Department of Pediatric Dentistry, Faculty of Dentistry, Süleyman Demirel University, Isparta, Turkey, within the period from March to July 2016. Although the questionnaire part involved 126 children with autism and 111 children without autism, 63 children who did not satisfy the inclusion criteria were excluded from the study in the interview part. The forms were sent to previously determined schools, and factors such as age, socioeconomic status, medical history, dental history, eating habits, bad habits, and treatment methods preferred by children's parents were analyzed. Later, interviews with the children were carried out by the same researcher and their oral health conditions were recorded. Children with autism often have nutritional problems, and early initiation of special education appears effective in preventing these conditions. Although children with autism apply for dental services, the rate for these children receiving dental services is considerably low and most of the services rendered are tooth extractions. It appears that the oral status of children with autism is affected negatively by many factors. Thus, the parents, the educators, and the dentists should be aware of this fact and encouraged to improve such children's oral hygiene and provide the dental care they need.


Switched alternative splicing of oncogene CoAA during embryonal carcinoma stem cell differentiation.
Alternative splicing produces functionally distinct proteins participating in cellular processes including differentiation and development. CoAA is a coactivator that regulates transcription-coupled splicing and its own pre-mRNA transcript is alternatively spliced. We show here that the CoAA gene is embryonically expressed and alternatively spliced in multiple tissues to three splice variants, CoAA, CoAM and CoAR. During retinoic-acid-induced P19 stem cell differentiation, the expression of CoAA undergoes a rapid switch to its dominant negative splice variant CoAM in the cavity of the embryoid body. CoAM functionally inhibits CoAA, and their switched expression up-regulates differentiation marker Sox6. Using a CoAA minigene cassette, we find that the switched alternative splicing of CoAA and CoAM is regulated by the cis-regulating sequence upstream of the CoAA basal promoter. Consistent to this, we show that p54(nrb) and PSF induce CoAM splice variant through the cis-regulating sequence. We have previously shown that the CoAA gene is amplified in human cancers with a recurrent loss of this cis-regulating sequence. These results together suggest that the upstream regulatory sequence contributes to alternative splicing of the CoAA gene during stem cell differentiation, and its selective loss in human cancers potentially deregulates CoAA alternative splicing and alters stem cell differentiation.


Expression of the aging gene p66Shc is increased in peripheral blood monocytes of patients with acute coronary syndrome but not with stable coronary artery disease.
The interplay between oxidative stress and inflammation is crucial in the pathogenesis of atherosclerosis. The adaptor protein p66Shc is implicated in atherogenesis and oxidative stress related responses in animal models of diseases. However, its role in humans remains to be defined. In this study, we hypothesized that expression of p66Shc increases in peripheral blood monocytes of patients affected by acute coronary syndromes (ACS). Male subjects aged 59±4 (mean±SD) years admitted for cardiac catheterization were subdivided in three groups: (a) no local stenosis for the control group, (b) at least one stenosis ≥75% in either left, circumflex or right coronary artery for the coronary artery disease (CAD) group or (c) ST-elevation/non-ST-elevation myocardial infarction for the ACS group. Monocytes were isolated from whole blood and p66Shc RNA levels were determined by quantitative real time PCR. p66Shc RNA levels were increased in ACS patients as compared to CAD (p=0.007) and controls (p=0.0249). Furthermore, malondialdehyde (MDA) and C-reactive protein (CRP) were increased in plasma of ACS patients. Levels of MDA correlated positively to p66Shc (r=0.376, p=0.01). Our data demonstrate increased p66Shc levels in monocytes of ACS but not CAD patients. This study suggests an involvement of p66Shc in the transition of a stable CAD to an ACS patient. p66Shc was associated with states of increased oxidative stress. Further work is needed to understand whether p66Shc may represent a possible pharmacological target or whether it represents an interesting novel biomarker.