Acute spontaneous spinal subdural hematoma presenting with Takotsubo cardiomyopathy: a rare case report and literature review.
Spontaneous spinal subdural hematoma (SSDH) is a rare and dangerous intraspinal hematoma that usually occurs in the thoracic vertebra. The influence of early cardiovascular changes secondary to spinal cord injury is an important emergent issue. Herein, we report a case of a middle-aged woman with clinical manifestations of back pain and motion and sensory disturbances below the level of spinal cord compression. During the disease course, she also developed changes indicative of myocardial injury, such as tachycardia, markedly increased concentrations of brain natriuretic peptide and cardiac troponin I, and a decreased left ventricular ejection fraction, which were consistent with the diagnosis of Takotsubo cardiomyopathy (TTC). After the administration of supportive therapies, the symptoms of myocardial injury rapidly resolved. With the absorption of SSDH, the symptoms and clinical signs were alleviated. We also reviewed the literature on cases of concomitant SSDH and TTC. This rare case broadens the symptom spectrum of SSDH and highlights the need for clinicians to be aware of concomitant SSDH and TTC. Initial conservative treatment is a viable option for SSDH with concomitant TTC. However, urgent surgery may be a better option if the SSDH progressively enlarges and causes spinal cord compression.


Application of the baby friendly hospital initiative to neonatal care: suggestions by Swedish mothers of very preterm infants.
The aim of this study was to obtain suggestions from mothers of very preterm infants regarding modification of the Baby Friendly Hospital Initiative (BFHI) 10 Steps to Successful Breastfeeding. Thirteen mothers were interviewed 2 to 6 months after their infants' discharge from the hospital. The interviews generated 13 steps, which partly agree with the BFHI steps. The new steps address respect for mothers' individual decisions about breastfeeding, education of staff in specific knowledge and skills, antenatal information about lactation in the event of preterm birth, skin-to-skin (kangaroo mother) care, breast milk expression, early introduction of breastfeeding, facilitation of mothers' 24-hour presence in the hospital, preference for mother's own milk, semi-demand feeding before transition to demand breastfeeding, special benefits of pacifier sucking, alternative strategies for reduction of supplementation, use of bottle-feeding when indicated, a family-centered and supportive physical environment, support of the father's presence, and early transfer of infants' care to parents.


Serum 25-hydroxyvitamin D3 is associated with advanced glycation end products (AGEs) measured as skin autofluorescence: The Rotterdam Study.
Advanced glycation end products (AGEs) accumulate in tissues with aging and may influence age-related diseases. They can be estimated non-invasively by skin autofluorescence (SAF) using the AGE Reader™. Serum 25-hydroxyvitamin D3 (25(OH)D3) may inhibit AGEs accumulation through anti-oxidative and anti-inflammatory properties but evidence in humans is scarce. The objective was to investigate the association between serum 25(OH)D3 and SAF in the population-based cohort study. Serum 25(OH)D3 and other covariates were measured at baseline. SAF was measured on average 11.5 years later. Known risk factors for AGE accumulation such as higher age, BMI, and coffee intake, male sex, smoking, diabetes, and decreased renal function were measured at baseline. Linear regression models were adopted to explore the association between 25(OH)D3 and SAF with adjustment for confounders. Interaction terms were tested to identify effect modification. The study was conducted in the general community. 2746 community-dwelling participants (age ≥ 45 years) from the Rotterdam Study were included. Serum 25(OH)D3 inversely associated with SAF and explained 1.5% of the variance (unstandardized B = - 0.002 (95% CI[- 0.003, - 0.002]), standardized β = - 0.125), independently of known risk factors and medication intake. The association was present in both diabetics (B = - 0.004 (95% CI[- 0.008, - 0.001]), β = - 0.192) and non-diabetics (B = - 0.002 (95% CI[- 0.003, - 0.002]), β = - 0.122), both sexes, both smokers and non-smokers and in each RS subcohort. Serum 25(OH)D3 concentration was significantly and inversely associated with SAF measured prospectively, also after adjustment for known risk factors for high SAF and the number of medication used, but the causal chain is yet to be explored in future studies.Clinical Trial Registry (1) Netherlands National Trial Register: Trial ID: NTR6831 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 ). (2) WHO International Clinical Trials Registry Platform: under shared catalogue number NTR6831 ( www.who.int/ictrp/network/primary/en/ ).


Severe Aplastic Anemia Presenting as Neutropenic Sepsis.
A 40-year-old female with aplastic anemia presented with a gum abscess deteriorating into neutropenic sepsis. Infection is an incredibly rare initial manifestation of aplastic anemia even on a background of significant neutropenia, hence the uniqueness of this case. The patient's initial complaints were of a subacute history of heavy vaginal bleeding and unexplained bruising, however on examination in the emergency department the patient was also noted to be pyrexial with gingival hyperplasia and a left sided submandibular lymphadenopathy. Initial blood results were phoned through from the lab reporting pancytopenia, confirming clinical suspicion of neutropenic sepsis. Antibiotic therapy was commenced and maxillofacial review for her unrelenting jaw pain revealed a gum abscess ultimately requiring tooth extraction. The patient underwent bone marrow biopsy showing hypocellular marrow with erythroid-dominant, dysplastic hematopoiesis. A thorough panel of investigations to rule out secondary causes led to the diagnosis of aplastic anemia, for which the patient is currently being managed with oral ciclosporin plus eltrombopag-bridging therapy, plus counselling for the potential requirement for stem cell transplant.


Clinical Therapeutic Effect of Naloxone Combined with Hemodialysis on Acute Severe Alcoholism.
BACKGROUND The aim of this research was to investigate the treatment effect of naloxone combined with hemodialysis on acute severe alcoholism. MATERIAL AND METHODS We included 36 patients treated with naloxone combined with hemodialysis in Group I and 34 patients treated with naloxone without hemodialysis in Group II. The Glasgow coma scale (GCS) score, the consciousness recovery time, alanine amino transferase (ALT) level, and complications were analyzed. RESULTS Mean GCS score in Group I was higher than that in Group II, with a significant difference (P<0.05). The consciousness recovery time in Groups I and II were 3.0±0.8 h and 6.9±2.1 h, respectively, with a significant difference (P<0.05). After naloxone treatment and hemodialysis, the ALT level in Group I was lower than that in Group II (P<0.05). Moreover, the incidence of hepatic and renal function damages in Group I was smaller than that in Group II (P<0.05). Only 1 patient in Group I developed pneumonia, which was fewer than that in Group II, with a significant difference (P<0.05). CONCLUSIONS Naloxone combined with hemodialysis effectively reduces the central inhibition of alcohol, shortens consciousness recovery time, improves respiratory and cardiovascular function, decreases hepatic and renal function damages, and reduces the incidence of complications.


Engineered microRNA therapeutics.
Targeting of microRNAs that are overexpressed or replacement of microRNAs whose expression is lost are two distinct and novel approaches to treat disease(s) driven by microRNA dysregulation. This can be achieved by chemical modification of either a single stranded oligonucleotide called an antimiR or a double stranded nucleic acid molecule termed a microRNA mimic.With hundreds of microRNAs identified and knowledge of their role in disease becoming clearer there is the prospect, over the coming years, to harness engineered microRNA therapeutics to revolutionise the way diseases are treated.Both types of engineered microRNA therapeutics have advanced into clinical development with human proof of concept achieved with an anti-miR targeting miR-122 (one of the most abundant microRNAs in human hepatocytes that is utilised by the hepatitis C virus to enable its function and replication). Rather than targeting individual proteins or enzymes involved in human disease, an opportunity now exists to modulate multiple different proteins/enzymes which act in concert in the progression of disease.


The biocompatibility and anti-biofouling properties of magnetic core-multishell Fe@C NWs-AAO nanocomposites.
Soft-magnetic core-multishell Fe@C NWs-AAO nanocomposites were synthesized using anodization, electrodeposition and low-pressure chemical vapour deposition (CVD) at 900 °C. High chemical and mechanical stability is achieved by the conversion from amorphous to θ- and δ-Al2O3 phases above 600 °C. Moreover, the surface properties of the material evolve from bioactive, for porous AAO, to bioinert, for Fe@C NW filled AAO nanocomposite. Although the latter is not cytotoxic, cells do not adhere onto the surface of the magnetic nanocomposite, thus proving its anti-biofouling character.


Prothymosin-α Variants Elicit Anti-HIV-1 Response via TLR4 Dependent and Independent Pathways.
Prothymosin α (ProTα) (isoform 2: iso2) is a widely distributed, small acidic protein with intracellular and extracellular-associated functions. Recently, we identified two new ProTα variants with potent anti-HIV activity from CD8+ T cells and cervicovaginal lavage. The first is a splice variant of the ProTα gene known as isoB and the second is the product of ProTα pseudogene 7 (p7). Similarly to iso2, the anti-HIV activity of both variants is mediated by type I IFN. Here we tested whether the immunomodulatory activity of isoB and p7 are also TLR4 dependent and determined their kinetic of release in response to HIV-1 infection. Type I, type III, TNF-α and IL-6 mRNA inducing activity was determined in macrophages from wild type and TLR4 knockout mice treated with recombinant ProTα variants. Supernatants from mock and HIV infected cells were analyzed by mass spectrometry in positive and negative modes for the presence of ProTα variants. In silico structural and functional analysis of ProTα variants were performed. We show that both isoB and p7 upregulate IFN-β, IFN-λ1, IL-6, TNF-α and RANTES mRNAs in primary human macrophages. The potent stimulation of IFN-β by the recombinant ProTα variants in human macrophages is dependent on the TLR4 pathway, whereas the induction of TNF-α and IL-6 may also occur independently of TLR4, suggesting the interaction of ProTα variants with other signaling molecules/receptors. In silico analyses confirmed that the novel isoB and p7 variants are intrinsically disordered proteins, which lack the NLS and mass spectrometry showed release of ProTα variants within minutes post HIV-1 infection. These features are consistent with the function of ProTα variants as damage associate molecular patterns (DAMPs). Our findings indicate that ProTα variants strongly inhibit viral replication mainly, but not exclusively, through TLR4 signaling and that they are released within minutes of viral infection suggesting that they may function as DAMPs.


Protective effect of Potentilla anserina polysaccharide on cadmium-induced nephrotoxicity in vitro and in vivo.
The aim of this research was to investigate the antioxidant and anti-apoptotic activities of Potentilla anserina polysaccharide (PAP) on kidney damage induced by cadmium (Cd) in vitro and in vivo. PAP has been suggested to have anti-oxidation, anti-apoptosis, immunoregulation, antimicrobial, antitussive, and expectorant abilities. In this study, PAP was extracted and the major components of PAP were analyzed. It was shown that PAP pretreatment remarkably improved redox homeostasis, both in human embryonic kidney 293 (HEK293) cells and in BALB/c mice. Administration of PAP attenuated the mitochondrial dysfunction, degeneration, and fibrosis of kidney induced by Cd. Furthermore, PAP exhibited anti-apoptotic activity, which involved regulating both the mitochondria-mediated intrinsic apoptotic pathway and the death receptor-initiated extrinsic pathway. These results suggest that PAP is a potential therapeutic agent for Cd-induced nephrotoxicity.


Modulation of the platelet serotonin transporter by thermal balneotherapy: a study in healthy subjects.
Although the beneficial effects of balneotherapy have been recognized since a long time, a few information is available on the biological mechanisms underlying them and the subjective feelings of increased well-being and mood. The links between the serotonin (5-HT) system and mood prompted us to investigate the 5-HT platelet transporter (SERT), which is considered a reliable, peripheral marker of the same structure present in presynaptic neurons, in 30 healthy volunteers before (t0) and 30 minutes after (t1) thermal balneotherapy with ozonized water, as compared with a similar group who underwent a bath in non-mineral water. MATERIALS AN METHODS: The SERT was evaluated by means of the specific binding of 3H-paroxetine (3H-Par) to platelet membranes. Equilibrium-saturation binding data, the maximal binding capacity (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. The results showed that, while Bmax values did not change in both groups, the Kd values decreased significantly at t1 only in those subjects who bathed in ozonized water. The results of this study, while showing a decrease of the dissociation constant (Kd) which is the inverse of affinity constant, of 3H-Par binding to SERT in all subjects after balneotherapy and not in those bathing in normal water, suggest that SERT modifications may be related to a specific effect of ozonized water and, perhaps, also to the increased sense of well-being.


Fibroblast migration on fibronectin requires three distinct functional domains.
Mesenchymal cell movement is normally constrained; however, fibronectin can provide a pathway for stromal cell migration during embryogenesis, morphogenesis, and wound healing. Cells can adhere to fibronectin via integrin and nonintegrin receptors, which bind multiple unique peptide sequences. Synthetic peptides and recombinant proteins were used to delineate the functional domains needed for human fibroblast migration over fibronectin. The 9th and 10th fibronectin type III repeats, which contain RGD and PHSRN synergy cell attachment sequences, support almost maximal fibroblast attachment, but not migration of primary dermal fibroblasts. Specific sequences within the heparin domain and the IIICS region are also required for migration. These findings predict and additional data confirm the necessity for the cooperation of multiple integrin and nonintegrin receptors for fibroblast migration on fibronectin. Such stringency of migration most likely imposes an immense constraint on normal mesenchymal cell mobility in unperturbed tissue. Loss of such restraint may be critical for the migration cancer cells through the extracellular matrix.


Anodal tDCS and High-Frequency tRNS Targeting the Occipitotemporal Cortex Do Not Always Enhance Face Perception.
There has been increasing interest in the utility of transcranial electrical stimulation as a tool to enhance cognitive abilities. In the domain of face perception, enhancements have been reported for both transcranial direct current stimulation (tDCS) and high-frequency transcranial random noise stimulation (tRNS) targeting the occipitotemporal cortex. In a series of two experiments, we attempted to replicate these findings for face identity perception, and extend on previous studies, to determine if similar enhancements are also observed for object and facial expression perception. In Experiment 1, using a single blind, between-subjects design in healthy volunteers (N = 53), we examined whether anodal tDCS over the occipitotemporal cortex enhanced performance on tasks involving perception of face identity, facial expression, and object stimuli, when compared to sham stimulation. We failed to replicate previous findings of enhanced performance on face and object perception, nor extend findings to facial expression perception. In Experiment 2, using a single blind, between-subjects design (N = 39), we examined the effect of high-frequency tRNS over the occipitotemporal cortex using the same three tasks employed in Experiment 1. We failed to replicate previous findings of enhanced face perception following high-frequency tRNS over the occipitotemporal cortex, relative to sham stimulation (although we used different stimulation parameters to that employed in a previous study). We also found no evidence of enhanced facial expression and object perception following high-frequency tRNS. The findings align with a growing body of studies that have failed to replicate previously reported enhancements following administration of tDCS and hint for different efficacy of, on first sight, related stimulation protocols. Future studies should explore the foundation of these differential effects in greater detail.


Microcontainers as an oral delivery system for spray dried cubosomes containing ovalbumin.
The purpose of this study was to prepare cubosomes encapsulating the model antigen ovalbumin (OVA) via spray drying, and to characterise such cubosomes with a view for their potential application in oral vaccine delivery. Furthermore the cubosome formulation was loaded into polymeric microcontainers intended as an oral drug delivery system. The cubosomes consisted of commercial glyceryl monooleate, Dimodan®, containing OVA and were surrounded with a dextran shell prepared by spray drying. Cryo-TEM was used to confirm that cubosomes were formed after hydration of the spray dried precursor powder. The precursor powder had a mean particle size of 1.3±0.1μm, whereas the mean diameter of the dispersed cubosomes was 282±7nm (PDI: 0.18) measured by dynamic light scattering. 8.5±0.3% (w/w) of OVA was present in the cubosome powder and OVA was found released slowly over the first 70h, followed by a more rapid release. Total release of 47.9±2.8% of loaded OVA occurred over 96h in a buffer at pH 6.8. When the powder was filled into microcontainers, and the opening covered with the pH sensitive polymer Eudragit S100, the pH sensitive 'lid' was intact at gastric pH, but release of OVA from the cubosomes and microcontainers occurred at pH 6.8, releasing 44.1±5.6% of the OVA in 96h. Small-angle X-ray scattering (SAXS) revealed that the 'dry' particles possessed an internal ordered lipid structure (lamellar and inverse micellar phase) by virtue of a small amount of residual water, and after hydration in buffer at pH 6.8, the particles formed the hexagonal inverse cubic phases, thereby indicating that cubosomes were formed when released from microcontainers.


Visual recovery following optic nerve decompression for chronic compressive neuropathy.
Visual failure due to optic nerve compression is a common indication for decompressive surgery. Most data only refer to the odds of improvement, deterioration or remaining the same. However, patients frequently wish to know more detail about the outcomes of surgery. Our aim was to assess the visual outcome from optic nerve decompression for visual failure in detail in order to help counsel patients pre-operatively. Sixty-eight patients undergoing 71 operations to decompress 87 optic nerves between 1991 and 2007 were identified. Thirty-four decompressions were performed via a transzygomatic and 37 via a transbasal approach. Fifty-two patients had meningiomas, 3 pituitary adenomas, 3 craniopharyngiomas, 3 chordomas, 2 adenocarcinomas, 2 fibrous dysplasia, 1 schwannoma, 1 granular pituitary tumour and 1 olfactory neuroblastoma. Visual acuity and fields were recorded pre-operatively, immediately post-operatively, at first follow-up and at most recent follow-up. Forty-three eyes (49.4%) experienced an improvement in either acuity or fields. Twenty-four (27.5%) were unchanged and 20 (22.9%) deteriorated. Average improvement was 0.88 Snellen lines (logMAR 0.13). Improvement was seen between immediate post-operative acuity and first follow-up in 52%, but 22% suffered a late deterioration after 1 year. There was no relationship between age, duration of symptoms, pathology, approach or redo surgery and visual outcome. There was a complex relationship between pre-operative visual acuity and post-operative improvement and outcome. Better pre-operative acuity predicted better outcome and greater odds of improvement, although patients with poor pre-operative vision had a greater average magnitude of improvement. Patients experience significant benefit from optic nerve decompression irrespective of pre-operative visual status. Although early decompression is desirable, good results can still be obtained in patients with severe visual failure. Detailed data on visual outcome can help counsel patients pre-operatively to aid decision-making and set expectations.


The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA.


A software tool to automatically assure and report daily treatment deliveries by a cobalt-60 radiation therapy device.
The aims of this study were to develop a method for automatic and immediate verification of treatment delivery after each treatment fraction in order to detect and correct errors, and to develop a comprehensive daily report which includes delivery verification results, daily image-guided radiation therapy (IGRT) review, and information for weekly physics reviews. After systematically analyzing the requirements for treatment delivery verification and understanding the available information from a commercial MRI-guided radiotherapy treatment machine, we designed a procedure to use 1) treatment plan files, 2) delivery log files, and 3) beam output information to verify the accuracy and completeness of each daily treatment delivery. The procedure verifies the correctness of delivered treatment plan parameters including beams, beam segments and, for each segment, the beam-on time and MLC leaf positions. For each beam, composite primary fluence maps are calculated from the MLC leaf positions and segment beam-on time. Error statistics are calculated on the fluence difference maps between the plan and the delivery. A daily treatment delivery report is designed to include all required information for IGRT and weekly physics reviews including the plan and treatment fraction information, daily beam output information, and the treatment delivery verification results. A computer program was developed to implement the proposed procedure of the automatic delivery verification and daily report generation for an MRI guided radiation therapy system. The program was clinically commissioned. Sensitivity was measured with simulated errors. The final version has been integrated into the com-mercial version of the treatment delivery system. The method automatically verifies the EBRT treatment deliveries and generates the daily treatment reports. Already in clinical use for over one year, it is useful to facilitate delivery error detection, and to expedite physician daily IGRT review and physicist weekly chart review.


Clinicopathological Correlation and Prevalence of Increased Copper in Canine Hepatic Cytology.
Special staining and grading of canine liver cytology samples aids in detection of increased copper content. The prevalence of copper in routine diagnostic liver cytology samples, clinical findings associated with high cytologic copper (cCu) grade, and the correlation between cCu grade and histologic findings, including histologic copper (hCu) grade, are unknown. This data may be helpful in ascertaining when to determine a cCu grade and when interpreting cCu grade. Clinical data and available archived hepatic histologic and cytologic samples from 198 dogs were collected, evaluated, rhodanine stained, and graded for copper. Prevalence of increased cCu >5 in a randomly collected group of 163 individuals, and the correlation between cCu and clinical data (n = 198), hCu grade (n = 37), or findings on hematoxylin and eosin-stained hepatic sections (n = 32) were evaluated. The observed prevalence was 1.23%. Dogs with elevated alanine transaminase >180 IU/L or aspartate transaminase >90 IU/L and patients who subsequently had hepatic copper quantification were statistically more likely to have pathologic levels of copper detected by cytology. There was significant and modest correlation between cCu and hCu, interface hepatitis, portal inflammation, and fibrosis. Evidence of hepatocellular leakage may be indications for determination of cCu.


Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes.
The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.


Melatonin Relations With Respiratory Quotient Weaken on Acute Exposure to High Altitude.
High altitude (HA) exposure may affect human health and performance by involving the body timing system. Daily variations of melatonin may disrupt by HA exposure, thereby possibly affecting its relations with a metabolic parameter like the respiratory quotient (RQ). Sea level (SL) volunteers (7 women and 7 men, 21.0 ± 2.04 y) were examined for daily changes in salivary melatonin concentration (SMC). Sampling was successively done at SL (Antofagasta, Chile) and, on acute HA exposure, at nearby Caspana (3,270 m asl). Saliva was collected in special vials (Salimetrics Oral Swab, United Kingdom) at sunny noon (SMCD) and in the absence of blue light at midnight (SMCN). The samples were obtained after rinsing the mouth with tap water and were analyzed for SMC by immunoassay (ELISA kit; IBL International, Germany). RQ measurements (n = 12) were realized with a portable breath to breath metabolic system (OxiconTM Mobile, Germany), between 8:00 PM and 10:00 PM, once at either location. At SL, SMCD, and SMCN values (mean ± SD) were, respectively, 2.14 ± 1.30 and 11.6 ± 13.9 pg/ml (p < 0.05). Corresponding values at HA were 8.83 ± 12.6 and 13.7 ± 16.7 pg/ml (n.s.). RQ was 0.78 ± 0.07 and 0.89 ± 0.08, respectively, at SL and HA (p < 0.05). Differences between SMCN and SMCD (SMCN-SMCD) strongly correlate with the corresponding RQ values at SL (r = -0.74) and less tight at HA (r = -0.37). Similarly, mean daily SMC values (SMC) tightly correlate with RQ at SL (r = -0.79) and weaker at HA (r = -0.31). SMCN-SMCD, as well as, SMC values at SL, on the other hand, respectively, correlate with the corresponding values at HA (r = 0.71 and r = 0.85). Acute exposure to HA appears to loosen relations of SMC with RQ. A personal profile in daily SMC variation, on the other hand, tends to be conserved at HA.


Chimpanzee histology and functional brain imaging show that the paracingulate sulcus is not human-specific.
The paracingulate sulcus -PCGS- has been considered for a long time to be specific to the human brain. Its presence/absence has been discussed in relation to interindividual variability of personality traits and cognitive abilities. Recently, a putative PCGS has been observed in chimpanzee brains. To demonstrate that this newly discovered sulcus is the homologue of the PCGS in the human brain, we analyzed cytoarchitectonic and resting-state functional magnetic resonance imaging data in chimpanzee brains which did or did not display a PCGS. The results show that the organization of the mid-cingulate cortex of the chimpanzee brain is comparable to that of the human brain, both cytoarchitectonically and in terms of functional connectivity with the lateral frontal cortex. These results demonstrate that the PCGS is not human-specific but is a shared feature of the primate brain since at least the last common ancestor to humans and great apes ~6 mya.


Injury Surveillance During Competitive Functional Fitness Racing Events.
High-intensity functional training (HIFT) is an exercise training modality that has grown considerably in popularity over the last decade. More recently, competitive functional fitness racing events have emerged from HIFT, and aim to test athletes' proficiency across a variety of movements, skills, and energy systems. Whilst the injury risk associated with HIFT has been shown to be low and comparable to other forms of recreational fitness activities, the injury risk associated with competitive functional fitness racing events is currently unknown. A prospective cohort design was used to record medical-attention injuries during two competitive functional fitness racing events, involving 1085 competitors. A total of 26 injuries were recorded over the two competitions, resulting in an injury incidence rate of 36 per 1000 competition hours (90% confidence limits [CL]: 26-50) and injury prevalence of 2.4% (90% CL: 1.6-3.2%). The shoulder (n=4) and hand (n=4) were the most commonly injured body locations. The incidence rate in male athletes was likely higher than female athletes (Rate Ratio [RR]: 1.87, 90% CL: 0.95-3.69). The injury incidence rate associated with competitive functional fitness racing events is higher than for HIFT training activities, though the injury prevalence is relatively low in comparison to other sporting activities. Further research is required to understand the burden of these injuries, and identify appropriate injury prevention strategies for this emerging sport.


The use of mouthguards in grappling sports: a survey of grapplers in the United Kingdom.
Background Mouthguards are routinely used in many sports, however their use in grappling sports has not really been examined to date, and to the authors' knowledge, there is no available data on the level of dental trauma experienced by this group.Materials and method The authors approached six different grappling schools, as well as leaving an invite on a grappling event page for volunteers to fill out a short survey.Results Around 81 respondents took part in the survey, with nearly 25% reporting that they never wore a mouthguard during grappling, and less than 50% not wearing a mouthguard all the time. Sixty-three percent of respondents had either seen dental and peri-oral injuries, or had experienced dental injuries as a result of grappling.Conclusion More work is needed to investigate whether mouthguards have a positive effect on the dental injury experience, and to establish the percentage of grapplers who at some point will be affected by dental trauma.


Culture's building blocks: investigating cultural evolution in a LEGO construction task.
ONE OF THE MOST ESSENTIAL BUT THEORETICALLY VEXING ISSUES REGARDING THE NOTION OF CULTURE IS THAT OF CULTURAL EVOLUTION AND TRANSMISSION: how a group's accumulated solutions to invariant challenges develop and persevere over time. But at the moment, the notion of applying evolutionary theory to culture remains little more than a suggestive trope. Whereas the modern synthesis of evolutionary theory has provided an encompassing scientific framework for the selection and transmission of biological adaptations, a convincing theory of cultural evolution has yet to emerge. One of the greatest challenges for theorists is identifying the appropriate time scales and units of analysis in order to reduce the intractably large and complex phenomenon of "culture" into its component "building blocks." In this paper, we present a model for scientifically investigating cultural processes by analyzing the ways people develop conventions in a series of LEGO construction tasks. The data revealed a surprising pattern in the selection of building bricks as well as features of car design across consecutive building sessions. Our findings support a novel methodology for studying the development and transmission of culture through the microcosm of interactive LEGO design and assembly.


Fasciatherapy and Reflexology compared to Hypnosis and Music Therapy in Daily Stress Management.
Patients suffering from stress symptoms due to every-day life who are looking for a non-pharmacological response to their relief expectation are many. Furthermore, early reckoning of the day-to-day stress which may lead to clinical diagnosis is the best way of preventing the stress-related diseases. Among the many alternative medicinal options, there is little evidence that fasciatherapy (Fs) and reflexology (Rf) are effective in this field. assess incidence of fasciatherapy Danis Bois Method (DBM) and of reflexology on patients' stress level in everyday-life, and provide a more informed choice among the numerous mind and body techniques by comparing them with hypnosis (Hp) and music therapy (Mt). Specialized Complementary and Alternative Medicine (CAM) centres for outpatients. 308 individuals (average age = 50.53 SD 14.37, 93 males, 215 females) going to the centres for health care, but free from serious diseases and not heavily medicated respecting the inclusion criteria and providing valid forms. Four armed, non-randomized observational pragmatic trial with pretest-posttest repeated measures, on separate samples of natural groups. According to the centre participants where they used to be treated, they were exposed to a single semi-standardized session of a technique of their choice: Fs, Rf, Hp, Mt. Volunteers had a controlled non-intervention resting (Rt) session. Mean STAI-Y assessing anxiety as reflecting the stress level: MANCOVA and ANCOVA performed with Tukey's HSD. MANCOVA indicates a significant reduction of anxiety (p < .01) in each condition, resting included. ANCOVA performance adjusting on stress level in T0 (41.73) and on the mean sumscore of the trait (44.89), Fs (-13.92), Rf (-15.92), and Hp (-15.88) were equally effective on the stress level decrease. Mt (-10.0) and Rt (-6.38) showed the same level of effectiveness. The results suggest fasciatherapy DBM, hypnosis, and reflexology could be used as non-pharmacological and safe interventions in stress management. Though showing a lesser efficiency, music therapy could be useful in different circumstances.


The molecular mechanism of nuclear transport revealed by atomic-scale measurements.
Nuclear pore complexes (NPCs) form a selective filter that allows the rapid passage of transport factors (TFs) and their cargoes across the nuclear envelope, while blocking the passage of other macromolecules. Intrinsically disordered proteins (IDPs) containing phenylalanyl-glycyl (FG)-rich repeats line the pore and interact with TFs. However, the reason that transport can be both fast and specific remains undetermined, through lack of atomic-scale information on the behavior of FGs and their interaction with TFs. We used nuclear magnetic resonance spectroscopy to address these issues. We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment. Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the NPC.


Managing capacity and demand in a resource constrained environment: lessons for the NHS?
The purchaser-provider split within the NHS which emerged out of the government's 1990 White Paper, Working for Patients, together with the introduction of the Patients Charter, has imposed new, tighter performance measures on provider units. The internal market has placed clear contractual guarantees on providers in terms of service/care provided. The Patients Charter has set, with little reference to local conditions, required timescales for treatment, i.e. waiting time guarantees for patients. The government is committed to reducing these guaranteed waiting times further. Both these factors have forced provider units to look far more closely at the way they operate, and the way they provide services. The impact of these performance measures has been magnified by the tight budgetary constraints within which provider units are currently expected to operate. Consequently the option of increasing service provision through expanding facilities and staff has effectively been precluded in the majority of instances. Thus provider units have been forced into reappraising the manner in which service provision is structured and the services delivered. While this restructuring of service provision has been most obvious in those services where the internal market has had the more immediate effect - for example, direct access services such as physiotherapy - increasingly, performance measure pressures have forced providers to examine the processes by which they deliver both in-patient and out-patient care. Analyses the difficulties encountered by an NHS Trust in Scotland in managing capacity and demand in a specialist out-patient clinic.


Antimicrobial-Resistant Klebsiella pneumoniae Carriage and Infection in Specialized Geriatric Care Wards Linked to Acquisition in the Referring Hospital.
Klebsiella pneumoniae is a leading cause of extended-spectrum β-lactamase (ESBL)-producing hospital-associated infections, for which elderly patients are at increased risk. We conducted a 1-year prospective cohort study, in which a third of patients admitted to 2 geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole-genome sequencing and antimicrobial susceptibility testing. K. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8%, and ESBL carriage 1.7%, and the incidence of K. pneumoniae infection was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15 and belonged to clones associated with hospital-acquired ESBL infections in other countries (sequence type [ST] 29, ST323, and ST340). One also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital. The data suggest the major source of K. pneumoniae was the patient's own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection prevention. Rectal screening for ESBL organisms on admission to geriatric wards could help inform patient management and infection control in such facilities.


Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: A multicentre experience.
To describe the ECPR experience of two Australian ECMO centres, with regards to survival and neurological outcome, their predictors and complications. Retrospective observational study of prospectively collected data on all patients who underwent extracorporeal cardiopulmonary resuscitation (ECPR) at two academic ECMO referral centres in Sydney, Australia. Thirty-seven patients underwent ECPR, 25 (68%) were for in-hospital cardiac arrests. Median age was 54 (IQR 47-58), 27 (73%) were male. Initial rhythm was ventricular fibrillation or pulseless ventricular tachycardia in 20 patients (54%), pulseless electrical activity (n=14, 38%), and asystole (n=3, 8%). 27 (73%) arrests were witnessed and 30 (81%) patients received bystander CPR. Median time from arrest to initiation of ECMO flow was 45min (IQR 30-70), and the median time on ECMO was 3days (IQR 1-6). Angiography was performed in 54% of patients, and 27% required subsequent coronary intervention (stenting or balloon angioplasty 24%). A total of 13 patients (35%) survived to hospital discharge (IHCA 33% vs. OHCA 37%). All survivors were discharged with favourable neurological outcome (Cerebral Performance Category 1 or 2). Pre-ECMO lactate level was predictive of mortality OR 1.35 (1.06-1.73, p=0.016). In selected patients with refractory cardiac arrest, ECPR may provide temporary support as a bridge to intervention or recovery. We report favourable survival and neurological outcomes in one third of patients and pre-ECMO lactate levels predictive of mortality. Further studies are required to determine optimum selection criteria for ECPR.


Acceptability and feasibility of infant-feeding options: experiences of HIV-infected mothers in the World Health Organization Kesho Bora mother-to-child transmission prevention (PMTCT) trial in Burkina Faso.
In Burkina Faso, prolonged breastfeeding with introduction of ritual fluids from birth is a deep-seated norm. We explored HIV-infected mothers' views and experiences of the acceptability and feasibility of the World Health Organization's recommended infant-feeding options within a mother-to-child-transmission prevention trial. A qualitative study was conducted on 17 formula-feeding and 19 breastfeeding mothers, from a larger cohort of 51 eligible HIV-infected women, consenting to participate in separate focus group discussions in early post-partum. Mothers opted for breastfeeding essentially out of fear of family rejection. Most of them were afraid of denigration for disrespecting tradition if they formula-fed or being suspected of HIV infection. Achieving exclusive breastfeeding remained a difficult challenge as they engaged in a continuous struggle with close elders to avoid fluid feeding. Additional stress and fatigue were fed by their perception of a high transmission risk through breast milk. Exclusive formula-feeding seemed easier to implement, especially as formula was provided free of charge. Formula-feeding mothers more frequently had a supportive partner, a strong personality and lived in better socio-economic conditions than breastfeeding mothers (76% had education and electricity supply vs. 42%, respectively). Exclusive breastfeeding for the first 6 months remains the most appropriate option for many HIV-infected mothers in sub-Saharan Africa. Its acceptability and feasibility urgently need to be improved by promoting it as the best feeding option for all infants. Other crucial interventions are the promotion of voluntary counselling and testing for couples, and greater partner involvement in infant-feeding counselling.


Exercise therapies in peripheral neuropathies.
The treatment of peripheral neuropathies should be aimed at maintaining the range of motion of the joints, re-educating the patient in skilled activities and optimizing the recovery of strength. Many techniques have been described to substitute for, to strengthen and to improve the function of residual innervated muscle; however, not all of these techniques are of unquestioned value. Specifically, electrical stimulation does not appear to enhance reinnervation of totally denervated muscle. Similarly, overstretching weakened muscle may impair the use of paretic muscle. Because overwork may damage partially denervated muscle, brief isometric or isotonic contractions may be more beneficial for increasing strength than a program of habitual exhausting activities.


Not so hot "hot spots" in the oceanic mantle.
Excess volcanism and crustal swelling associated with hot spots are generally attributed to thermal plumes upwelling from the mantle. This concept has been tested in the portion of the Mid-Atlantic Ridge between 34 degrees and 45 degrees (Azores hot spot). Peridotite and basalt data indicate that the upper mantle in the hot spot has undergone a high degree of melting relative to the mantle elsewhere in the North Atlantic. However, application of various geothermometers suggests that the temperature of equilibration of peridotites in the mantle was lower, or at least not higher, in the hot spot than elsewhere. The presence of H(2)O-rich metasomatized mantle domains, inferred from peridotite and basalt data, would lower the melting temperature of the hot spot mantle and thereby reconcile its high degree ofmelting with the lack of a mantle temperature anomaly. Thus, some so-called hot spots might be melting anomalies unrelated to abnormally high mantle temperature or thermal plumes.


Cognitive Deficits Associated with Sleep Apnea in Myotonic Dystrophy Type 1.
Although sleep-disordered breathing and cognitive impairment are common features of patients with myotonic dystrophy type 1 (DM1), little is known about their relationship. Forty-three adult DM1 patients underwent 2 sequential polysomnographic sessions and a neuropsychological test battery (intellectual functioning, attention, language, memory, and executive functions). Lower scores in attention, vigilance, and executive functioning tests were associated with higher number of apneic/hypopneic episodes per hour of sleep and longer total sleep time at an oxyhemoglobin saturation of less than 90%. Results suggest a potential role for nighttime breathing problems in the cognitive impairment often observed in DM1 patients.


Perinatal mortality and mode of delivery in monochorionic diamniotic twin pregnancies ≥ 32 weeks of gestation: a multicentre retrospective cohort study.
To study perinatal mortality rates in a cohort of 465 monochorionic (MC) twins without twin-twin transfusion syndrome (TTS) born at 32 weeks of gestation or later since reported interauterine fetal death (IUFD) rates >32 weeks of gestations in the literature vary, leading to varying recommendations on the optimal timing of delivery, and to investigate the relation between perinatal mortality and mode of delivery. Multicentre retrospective cohort study. Ten perinatal referral centres in the Netherlands. All MC twin pregnancies without TTTS delivered at ≥ 32 weeks of gestation between January 2000 and December 2005. The medical records of all MC twin pregnancies without TTTS delivered at the ten perinatal referral centres in the Netherlands between January 2000 and December 2005 were reviewed. Perinatal mortality in relation to gestational age and mode of delivery at ≥ 32 weeks of gestation. After 32 weeks of gestation, five out of 930 fetuses died in utero and there were six neonatal deaths (6 per 1000 infants). In women who delivered ≥ 37 weeks, perinatal mortality was 7 per 1000 infants. Trial of labour was attempted in 376 women and was successful in 77%. There were three deaths in deliveries with a trial of labour (8 per 1000 deliveries), of which two were related to mode of delivery. Infants born by caesarean section without labour had an increased risk of neonatal morbidity and respiratory distress syndrome. In MC twin pregnancies the incidence of intrauterine fetal death is low ≥ 32 weeks of gestation. Therefore, planned preterm delivery before 36 weeks does not seem to be justified. The risk of intrapartum death is also low, at least in tertiary centres.


Meticillin resistance in orthopaedic coagulase-negative staphylococcal infections.
Orthopaedic infections due to coagulase-negative staphylococci (CoNS) and meticillin-resistant strains may be increasing. We assessed secular trends of CoNS infections and factors associated with meticillin resistance by performing a 13-year retrospective cohort study of orthopaedic patients with CoNS infections from January 1995 to December 2007. Of 60 CoNS infections, 57 (95%) were implant-related. Median follow-up after end of treatment was 5.1 years (range: 2.4-13.8). During the study period, 44,237 orthopaedic procedures were performed, 21,299 (48%) with implants. The overall cumulative incidence of CoNS-associated infection was 0.14% and 0.28% for implant-related procedures. There were non-significant changes in the absolute number or cumulative incidence of CoNS infection (chi-squared test, P values for trend: 0.45 and 0.97, respectively). Forty-five episodes (75%) were due to meticillin-resistant strains. The proportion of meticillin resistance remained stable over time (P for trend: 0.65). Whereas few (4/15) meticillin-susceptible strains were associated with prior prophylaxis that covered the causative pathogen, 28/45 meticillin-resistant strains were associated with inadequate prophylaxis (P=0.03). The cumulative incidence of orthopaedic CoNS infection is low and stable in our institution and almost exclusively implant-related. The proportion of meticillin resistance among CoNS has remained stable over the last decade with a favourable clinical outcome.


Optimization and evaluation of Flexicult® Vet for detection, identification and antimicrobial susceptibility testing of bacterial uropathogens in small animal veterinary practice.
Urinary tract infection (UTI) is a common reason for antimicrobial prescription in dogs and cats. The objective of this study was to optimize and evaluate a culture-based point-of-care test for detection, identification and antimicrobial susceptibility testing of bacterial uro-pathogens in veterinary practice. Seventy-two urine samples from dogs and cats with suspected UTI presenting to seven veterinary facilities were used by clinical staff and an investigator to estimate sensitivity and specificity of Flexicult Vet A compared to laboratory reference standards for culture and susceptibility testing. Subsequently, the test was modified by inclusion of an oxacillin-containing compartment for detection of methicillin-resistant staphylococci. The performance of the modified product (Flexicult Vet B) for susceptibility testing was evaluated in vitro using a collection of 110 clinical isolates. Bacteriuria was reported by the laboratory in 25 (35 %) samples from the field study. The sensitivity and specificity of Flexicult Vet A for detection of bacteriuria were 83 and 100 %, respectively. Bacterial species were correctly identified in 53 and 100 % of the positive samples by clinical staff and the investigator, respectively. The susceptibility results were interpreted correctly by clinical staff for 70 % of the 94 drug-strain combinations. Higher percentages of correct interpretation were observed when the results were interpreted by the investigator in both the field (76 %) and the in vitro study (94 %). The most frequent errors were false resistance to β-lactams (ampicillin, amoxicillin-clavulanate and cephalotin) in Escherichia coli for Flexicult Vet A, and false amoxicillin-clavulanate resistance in E. coli and false ampicillin susceptibility in Staphylococcus pseudintermedius for Flexicult Vet B. The latter error can be prevented by categorizing staphylococcal strains growing in the oxacillin compartment as resistant to all β-lactams. Despite the shortcomings regarding species identification by clinical staff and β-lactam susceptibility testing of E. coli, Flexicult Vet B (commercial name Flexicult(®) Vet) is a time- and cost-effective point-of-care test to guide antimicrobial choice and facilitate implementation of antimicrobial use guidelines for treatment of UTIs in small animals, provided that clinical staff is adequately trained to interpret the results and that clinics meet minimum standards to operate in-house culture.


Ablation of Complex Fractionated Electrograms Improves Outcome in Persistent Atrial Fibrillation of Over 2 Year's Duration.
There is controversy and sparse data on whether substrate based techniques in addition to pulmonary vein isolation (PVI) confer benefit in the catheter ablation of persistent atrial fibrillation (AF), especially if long standing. We performed an observational study to assess whether substrate based ablation improved freedom from atrial arrhythmia. A total of 286 patients undergoing first ablation procedures for persistent AF with PVI only(n = 79), PVI plus linear ablation(n = 85), or PVI plus complex fractionated electrogram (CFAE) and linear ablation(n = 107) were followed. Primary end point was freedom from atrial arrhythmia at one year. Mean duration of pre-procedure time in AF was 28+/-27 months.There were no differences in baseline characteristics between groups except a higher proportion of patients with a severely dilated LA in those receiving PVI+CFAEs+lines. Freedom from atrial arrhythmia was higher with a PVI+CFAE+lines strategy then for PVI alone (HR 1.56, 95% CI: 1.04-2.34, p=0.032) but was not higher with PVI+lines. Benefit of substrate modification was conferred for preprocedure times in AF of over 30 months. The occurrence of atrial tachycardia was higher when lines were added to the ablation strategy (HR 0.08, 95% CI: 0.01-0.59, p=0.014). Freedom from atrial arrhythmia at 1 year was higher with lower patient age, use of general anaesthetic (GA), normal or mildly dilated left atrium and decreasing time in AF. In patients with long standing persistent AF of over 30 months duration,CFAE ablation resulted in improved freedom from atrial arrhythmia. Increased freedom from atrial arrhythmia occurs in patients who are younger and have smaller atria, and with GA procedures. Linear ablation did not improve outcome and resulted in a higher incidence of atrial tachycardia.


Characteristics of mentally retarded criminal offenders in Northern Taiwan.
The characteristics and criminal behavior in mentally retarded individuals remain largely unstudied. This retrospective study sought to establish a set of reference of criminal behavior characteristics in an ethnic Chinese mentally retarded group. Data were collected from forensic psychiatric evaluation of 32 mentally retarded offenders. Of the 32 offenders, only four (12.5%) cases were female. Mean age at the time of the offenses was 31. By IQ testing, 23 (71.9%) of the group fell into the mild mental retardation range, seven (21.9%) into the moderate mental retardation range, and two (6.2%) into the severe mental retardation range. Nineteen (59.3%) of the group also suffered from additional mental disorder. Eight (25%) had definite neurological deficit. Fourteen (43.8%) were repeat offenders. A total of 24 (75%) of the offenders had committed crimes against property, with 13 having committed petty theft. Furthermore, the pattern of offending shows differences from that of the general population or other mental disorders. The property offenses, especially petty theft and arson, were frequently seen. There was no noteworthy above average frequency of sexual offenses.


Management of extra-articular fractures of the fifth metacarpal: Operative vs. Non-opeRaTive TrEatment (FORTE) - A systematic review and meta-analysis.
Extra-articular fifth metacarpal fractures are treated operatively and non-operatively without consensus. We aim to establish whether there are differences in patient-reported outcome, objective clinical outcome and adverse events for skeletally mature patients with closed extra-articular fractures of the 5th metacarpal that are treated operatively versus non-operatively. Skeletally mature patients with closed, extra-articular 5th metacarpal fractures. A systematic review and meta-analysis of randomised controlled trials using methodology adapted from the Cochrane Handbook for Systematic Review of Interventions and compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. (PROSPERO CRD42018091633). Two trials of 5th metacarpal neck fractures met the inclusion criteria and were included in the final pooled analysis (n = 125). There were no significant differences in patient-reported, objective clinical or radiographic outcomes between the operative and non-operative groups at 12 months. Operatively managed patients reported greater time off work and were more likely to suffer an adverse event. Existing trial data is limited and inconclusive in terms of patient-reported outcome measures. Given that there remains wide variation in the treatment of these common injuries around the world, there is a need for further high-quality evidence to guide clinical practice.


Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study.
Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.


The influence of oxygen delivery during cardiopulmonary bypass on the incidence of delirium in CABG patients; a retrospective study.
Postoperative delirium is the most common neurological complication of cardiac surgery. Hypoxia has been shown to increase the risk of postoperative delirium. The possibility to continuously monitor oxygen delivery (DO2) during cardiopulmonary bypass (CPB) offers an adequate approximation of the oxygen status in a patient. This study investigates the role of oxygen delivery during cardiopulmonary bypass in the incidence of postoperative delirium. Three hundred and fifty-seven adult patients who underwent normothermic coronary artery bypass grafting (CABG) surgery were included in this retrospective study. The nadir indexed DO2 (DO2i) value on bypass, the total time under the critical DO2i level and the area under the curve (AUC) for critical DO2i were determined. Delirium was identified by the postoperative administration of haloperidol. The mean nadir DO2i significantly differed, comparing the group of patients with postoperative delirium to the group without. Multivariate analysis only identified age, pre-existing cognitive impairment, preoperative kidney dysfunction and cross-clamp time as independent risk factors for delirium. The results also indicated that patients of older age were more sensitive to a declined DO2i. A low DO2i during cardiopulmonary bypass is significantly associated with the incidence of postoperative delirium in CABG patients. However, the role of DO2 as an independent predictor of delirium could not be proven.


Social Incentives and Gamification to Promote Weight Loss: The LOSE IT Randomized, Controlled Trial.
Social networks influence obesity patterns, but interventions to leverage social incentives to promote weight loss have not been well evaluated. To test the effectiveness of gamification interventions designed using insights from behavioral economics to enhance social incentives to promote weight loss. The Leveraging Our Social Experiences and Incentives Trial (LOSE IT) was a 36-week randomized, controlled trial with a 24-week intervention and 12-week follow-up. One hundred and ninety-six obese adults (body mass index ≥ 30) comprising 98 two-person teams. All participants received a wireless weight scale, used smartphones to track daily step counts, formed two-person teams with a family member or friend, and selected a weight loss goal. Teams were randomly assigned to control or one of two gamification interventions for 36 weeks that used points and levels to enhance collaborative social incentives. One of the gamification arms also had weight and step data shared regularly with each participant's primary care physician (PCP). The primary outcome was weight loss at 24 weeks. Secondary outcomes included weight loss at 36 weeks. At 24 weeks, participants lost significant weight from baseline in the control arm (mean: - 3.9 lbs; 95% CI: - 6.1 to - 1.7; P < 0.001), the gamification arm (mean: - 6.6 lbs; 95% CI: - 9.4 to - 3.9; P < 0.001), and the gamification arm with PCP data sharing (mean: - 4.8 lbs; 95% CI: - 7.4 to - 2.3; P < 0.001). At 36 weeks, weight loss from baseline remained significant in the control arm (mean: - 3.5 lbs; 95% CI: - 6.1 to - 0.8; P = 0.01), the gamification arm (mean: - 6.3 lbs; 95% CI: - 9.2 to - 3.3; P < 0.001), and the gamification arm with PCP data sharing (mean: - 5.2 lbs; 95% CI: - 8.5 to - 2.0; P < 0.01). However, in the main adjusted model, there were no significant differences in weight loss between each of the intervention arms and control at either 12, 24, or 36 weeks. Using digital health devices to track behavior with a partner led to significant weight loss through 36 weeks, but the gamification interventions were not effective at promoting weight loss when compared to control. clinicaltrials.gov Identifier: 02564445.


Accountable care organization formation is associated with integrated systems but not high medical spending.
Medicare's approximately 250 accountable care organizations (ACOs) care for a growing portion of all fee-for-service beneficiaries across the United States. We examined where ACOs have formed and what regional factors are predictive of ACO formation. Understanding these factors could help policy makers foster growth in areas with limited ACO development. We found wide variation in ACO formation, with large areas, such as the Northwest, essentially empty of ACOs, and others, such as the Northeast and Midwest, dense with the organizations. Key regional factors associated with ACO formation include a greater fraction of hospital risk sharing (capitation), larger integrated hospital systems, and primary care physicians practicing in large groups. Area income, Medicare per capita spending, Medicare Advantage enrollment rates, and physician density were not associated with ACO formation. Together, these results imply that underlying provider integration in a region may help drive the formation of ACOs.


Disease Ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data.
The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years. These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. This will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning.


Targeted computational probabilistic corroboration of experimental knee wear simulator: the importance of accounting for variability.
Experimental testing is widely used to predict wear of total knee replacement (TKR) devices. Computational models cannot replace this essential in vitro testing, but they do have complementary strengths and capabilities, which make in silico models a valuable support tool for experimental wear investigations. For effective exploitation, these two separate domains should be closely corroborated together; this requires extensive data-sharing and cross-checking at every stage of simulation and testing. However, isolated deterministic corroborations provide only a partial perspective; in vitro testing is inherently variable, and relatively small changes in the environmental and kinematic conditions at the articulating interface can account for considerable variation in the reported wear rates. Understanding these variations will be key to managing uncertainty in the tests, resulting in a 'cleaner' investigation environment for further refining current theories of wear. This study demonstrates the value of probabilistic in silico methods by describing a specific, targeted corroboration of the AMTI knee wear simulator, using rigid body dynamics software models. A deterministic model of the simulator under displacement-control was created for investigation. Firstly, a large sample of experimental data (N>100) was collated, and a probabilistic computational study (N>1000 trials) was used to compare the kinetic performance envelopes for in vitro and in silico models, to more fully corroborate the mechanical model. Secondly, corresponding theoretical wear-rate predictions were compared to the experimentally reported wear data, to assess the robustness of current wear theories to uncertainty (as distinct from the mechanical variability). The results reveal a good corroboration for the physical mechanics of the wear test rig; however they demonstrate that the distributions for wear are not currently well-predicted. The probabilistic domain is found to be far more sensitive at distinguishing between different wear theories. As such we recommend that in future, researchers move towards probabilistic studies as a preferred framework for investigations into implant wear.


In vivo and in vitro evaluation of the osteogenic potential of Davallia mariesii T. Moore ex Baker.
Postmenopausal osteoporosis is a major bone health issue worldwide. There is an unmet medical need for osteoporosis treatments, a disease which disproportionately impacts women. Exploring botanicals to prevent or treat osteoporosis is currently an interest of investigations. Rhizomes of Davallia mariesii T. Moore ex Baker (Davalliacea) are used an indigenous herbal medicine in Asia for injuries due to fractures, contusions, and strains. In the present study, we investigated the osteogenic effect of the water extract of rhizomes of D. mariesii (DMH) on bone loss induced by an ovariectomy (OVX) in mice and also its impact on osteogenesis in primary human osteoblasts (HObs). Additionally, we performed a quantitative analysis of compounds in the DMH extract. OVX C57BL/6J mice were orally administrated DMH extract for 12 weeks, and microarchitecture parameters were examined by microcomputed tomography. DMH extract was fractionated in a bio-guided manner, and fractions were isolated to obtain active compounds using HObs. Cell viability was evaluated by an MTT assay. Characteristics of early and late osteogenesis were analyzed by alkaline phosphatase activity and a mineralization assay. Molecular mechanisms were explored by a real-time quantitative PCR. Compounds in the DMH extract were identified and quantified using liquid chromatography tandem mass spectroscopy (LC-MS/MS). DMH improved bone mineral densities of vertebrae and the femur. Through microarchitectural observations, DMH significantly decreased the bone surface/volume ratio and trabecular separation, and also increased the connectivity density in the OVX group. Additionally, DMH inhibited osteoclast differentiation in receptor activator of nuclear factor-κB ligand-induced osteoclasts and increased bone formation in HObs. After bio-guided fractionation and isolation, we found that eriodictyol-7-O-β-d-glucuronide (2) significantly increased alkaline phosphatase activity, and 5-O-β-d-(6-O-vanilloylglucopyranosyl)gentisic acid (3) substantially enhanced mineral deposition. In HObs, compound 3 was more potent in upregulating expressions of bone morphogenetic protein-2, bone sialoprotein, osteopontin, osterix, and estrogen receptor-α. The amount of bioactive compound 3 in DMH was 5.68 ± 0.64 mg/g of dry weight according to LC-MS/MS. For the first time we report that D. mariesii and its isolated compounds demonstrated potent osteogenic activities. Quantitative results of D. mariesii could be a reference for phytochemical analyses.


Large outbreak of Salmonella enteritidis PT8 in Portsmouth, UK, associated with a restaurant.
Seventy-five individuals with Salmonella infection were identified in the Portsmouth area during August and September 2009, predominantly Salmonella Enteritidis phage type 8. Five patients were admitted to hospital. A case-case comparison study showed that a local restaurant was the most likely source of the infection with a risk of illness among its customers 25-fold higher than that of those who did not attend the restaurant. A case-control study conducted to investigate specific risk factors for infection at the restaurant showed that eating salad was associated with a threefold increase in probability of illness. Changing from using ready washed lettuces to lettuces requiring washing and not adhering strictly to the 48 hours exclusion policy for food handlers with diarrhoea were likely to have contributed to the initiation and propagation of this outbreak. Possibilities for cross-contamination and environmental contamination were identified in the restaurant.


Alternative models for the evolution of eyespots and of serial homology on lepidopteran wings.
Serial homology is widespread in organismal design, but the origin and individuation of these repeated structures appears to differ with the different types of serial homologues, and remains an intriguing and exciting topic of research. Here I focus on the evolution of the serially repeated eyespots that decorate the margin of the wings of nymphalid butterflies. In this system, unresolved questions relate to the evolutionary steps that lead to the appearance of these serial homologues and how their separate identities evolved. I present and discuss two alternative hypotheses. The first proposes that eyespots first appeared as a row of undifferentiated repeated modules, one per wing compartment, that later become individuated. This individuation allowed eyespots to appear and disappear from specific wing compartments and also allowed eyespots to acquire different morphologies. The second hypothesis proposes that eyespots first appeared as individuated single units, or groups of units, that over evolutionary time were co-opted into new compartments on the wing. I discuss the merits of each of these alternate hypotheses by finding analogies to other systems and propose research avenues for addressing these issues in the future.


Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis.
Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS. Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-beta) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months -2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-beta comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-beta comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-beta comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-beta comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production. Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-beta, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens. ClinicalTrials.gov NCT00616187.


Southern Ocean dust-climate coupling over the past four million years.
Dust has the potential to modify global climate by influencing the radiative balance of the atmosphere and by supplying iron and other essential limiting micronutrients to the ocean. Indeed, dust supply to the Southern Ocean increases during ice ages, and 'iron fertilization' of the subantarctic zone may have contributed up to 40 parts per million by volume (p.p.m.v.) of the decrease (80-100 p.p.m.v.) in atmospheric carbon dioxide observed during late Pleistocene glacial cycles. So far, however, the magnitude of Southern Ocean dust deposition in earlier times and its role in the development and evolution of Pleistocene glacial cycles have remained unclear. Here we report a high-resolution record of dust and iron supply to the Southern Ocean over the past four million years, derived from the analysis of marine sediments from ODP Site 1090, located in the Atlantic sector of the subantarctic zone. The close correspondence of our dust and iron deposition records with Antarctic ice core reconstructions of dust flux covering the past 800,000 years (refs 8, 9) indicates that both of these archives record large-scale deposition changes that should apply to most of the Southern Ocean, validating previous interpretations of the ice core data. The extension of the record beyond the interval covered by the Antarctic ice cores reveals that, in contrast to the relatively gradual intensification of glacial cycles over the past three million years, Southern Ocean dust and iron flux rose sharply at the Mid-Pleistocene climatic transition around 1.25 million years ago. This finding complements previous observations over late Pleistocene glacial cycles, providing new evidence of a tight connection between high dust input to the Southern Ocean and the emergence of the deep glaciations that characterize the past one million years of Earth history.


Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use.
The relationship between use of oral contraceptives (OCs) and other contraceptive methods and the risk of ovarian cancer was examined in a combined analysis of 3 hospital-based case-control studies conducted in Italy, the United Kingdom, and Greece, for a total of 971 ovarian cancer cases and 2,258 controls under age 65. Compared with never-users, the combined multivariate relative risk (RR) for ever-users was 0.6 (95% confidence interval, CI = 0.4-0.8) and the estimates were consistent in the 3 datasets. The protection was also similar across strata of age and parity. Considering various measures of OC use, available in the Italian and British datasets only, the protection conveyed on ovarian cancer risk increased with the duration of use and persisted in the medium-long period: the RR in women reporting their last OC use greater than or equal to 15 years prior to diagnosis was 0.5 (95% CI = 0.2-1.0). The risks in ever-users were appreciably lower in those women who reported their first OC use before 25 years of age (RR = 0.3 for first use before age 25, 0.8 for first use at age 25-34 and 0.7 at 35 years or after). Such findings emerged similarly from Italian and British data. This combined analysis, besides offering further quantitative estimates of the protective effects of OCs on ovarian cancer risk in European populations, provides useful insights into the time pattern of the relationship between OC use and ovarian carcinogenesis, suggesting that the protection persists for 15 years or more after cessation of use and may be larger for use at younger age.


Genomic resources for Myzus persicae: EST sequencing, SNP identification, and microarray design.
The green peach aphid, Myzus persicae (Sulzer), is a world-wide insect pest capable of infesting more than 40 plant families, including many crop species. However, despite the significant damage inflicted by M. persicae in agricultural systems through direct feeding damage and by its ability to transmit plant viruses, limited genomic information is available for this species. Sequencing of 16 M. persicae cDNA libraries generated 26,669 expressed sequence tags (ESTs). Aphids for library construction were raised on Arabidopsis thaliana, Nicotiana benthamiana, Brassica oleracea, B. napus, and Physalis floridana (with and without Potato leafroll virus infection). The M. persicae cDNA libraries include ones made from sexual and asexual whole aphids, guts, heads, and salivary glands. In silico comparison of cDNA libraries identified aphid genes with tissue-specific expression patterns, and gene expression that is induced by feeding on Nicotiana benthamiana. Furthermore, 2423 genes that are novel to science and potentially aphid-specific were identified. Comparison of cDNA data from three aphid lineages identified single nucleotide polymorphisms that can be used as genetic markers and, in some cases, may represent functional differences in the protein products. In particular, non-conservative amino acid substitutions in a highly expressed gut protease may be of adaptive significance for M. persicae feeding on different host plants. The Agilent eArray platform was used to design an M. persicae oligonucleotide microarray representing over 10,000 unique genes. New genomic resources have been developed for M. persicae, an agriculturally important insect pest. These include previously unknown sequence data, a collection of expressed genes, molecular markers, and a DNA microarray that can be used to study aphid gene expression. These resources will help elucidate the adaptations that allow M. persicae to develop compatible interactions with its host plants, complementing ongoing work illuminating plant molecular responses to phloem-feeding insects.


Feasibility study on image guided patient positioning for stereotactic body radiation therapy of liver malignancies guided by liver motion.
Fiducial markers are the superior method to compensate for interfractional motion in liver SBRT. However this method is invasive and thereby limits its application range. In this retrospective study, the compensation method for the interfractional motion using fiducial markers (gold standard) was compared to a new non-invasive approach, which does rely on the organ motion of the liver and the relative tumor position within this volume. We analyzed six patients (3 m, 3f) treated with SBRT in 2014. After fiducial marker implantation, all patients received a treatment CT (free breathing, without abdominal compression) and a 4D-CT (consisting of 10 respiratory phases). For all patients the gross tumor volumes (GTVs), internal target volume (ITV), planning target volume (PTV), internal marker target volumes (IMTVs) and the internal liver target volume (ILTV) were delineated based on the CT and 4D-CT images. CBCT imaging was used for the standard treatment setup based on the fiducial markers. According to the patient coordinates the 3 translational compensation values (t x , t y , t z ) for the interfractional motion were calculated by matching the blurred fiducial markers with the corresponding IMTV structures. 4 observers were requested to recalculate the translational compensation values for each CBCT (31) based on the ILTV structures. The differences of the translational compensation values between the IMTV and ILTV approach were analyzed. The magnitude of the mean absolute 3D registration error with regard to the gold standard overall patients and observers was 0.50 cm ± 0.28 cm. Individual registration errors up to 1.3 cm were observed. There was no significant overall linear correlation between the respiratory motion and the registration error of the ILTV approach. Two different methods to calculate the translational compensation values for interfractional motion in stereotactic liver therapy were evaluated. The registration accuracy of the ILTV approach is mainly limited by the non-rigid behavior of the liver and the individual registration experience of the observer. The ILTV approach lacks the accuracy that would be desired for stereotactic radiotherapy of the liver.


School-related sedentary behaviours and indicators of health and well-being among children and youth: a systematic review.
The purpose of this systematic review was to examine the associations between school-related sedentary behaviours and indicators of health and well-being in children and youth (~ 5-18 years) attending school. This review was conducted to inform the development of School-Related Sedentary Behaviour Recommendations. Peer-reviewed, published, or in-press articles in English were included. Reviews, meta-analyses, and case studies were excluded; all other study designs were eligible. Further, articles had to meet the a priori study criteria for population, intervention, comparator (PROSPERO ID: CRD42021227600). Embase, MEDLINE® ALL, and PsycINFO were searched. Risk of bias was assessed for individual experimental studies using the Cochrane risk of bias assessment tool, and in observational studies based on the GRADE framework and in line with previous systematic reviews examining sedentary behaviours in children. Overall quality of evidence was assessed using the GRADE framework for each outcome category and study design. Results were synthesized narratively, grouped by study design and outcome category. Further, several high-level summaries were conducted to help interpret results. Evidence was synthesized from 116 reports, including 1,385,038 participants and 1173 extracted associations. More school-related sedentary behaviour was favourably associated with nearly one-third of extracted associations for cognitive (33%) and social-emotional (32%) indicators (e.g., less anxiety), but unfavourably associated with other movement behaviours (e.g., less physical activity) (35%). Active lessons were favourable (72%), compared to more school-related sedentary behaviours, when examining associations for all health and well-being indicators. More homework was favourable across all health and well-being indicators in 4% of extracted associations for primary school children, and 25% of extracted associations for secondary school children. However, ≥2 h/day of homework appeared to be unfavourable for health and well-being. Limitations for synthesized studies included generally low quality of evidence and a lack of studies in South American, African, or low-middle income countries. Findings can help inform policy makers, schools, and teachers, regarding the amount of homework assigned and the introduction of active lessons into the classroom to enhance health and well-being of children. More research is needed examining school-related sedentary behaviours and indicators of health and well-being in low- and middle-income countries.


Enabling Precision Medicine through Integrative Network Models.
A key challenge in precision medicine lies in understanding molecular-level underpinnings of complex human disease. Biological networks in multicellular organisms can generate hypotheses about disease genes, pathways, and their behavior in disease-related tissues. Diverse functional genomic data, including expression, protein-protein interaction, and relevant sequence and literature information, can be utilized to build integrative networks that provide both genome-wide coverage as well as contextual specificity and accuracy. By carefully extracting the relevant signal in thousands of heterogeneous functional genomics experiments through integrative analysis, these networks model how genes work together in specific contexts to carry out cellular processes, thereby contributing to a molecular-level understanding of complex human disease and paving the way toward better therapy and drug treatment. Here, we discuss current methods to build context-specific integrative networks, focusing on tissue-specific networks. We highlight applications of these networks in predicting tissue-specific molecular response, identifying candidate disease genes, and increasing power by amplifying the disease signal in quantitative genetics data. Altogether, these exciting developments enable biomedical scientists to characterize disease from pathophysiology to cellular system and, finally, to specific gene alterations-making significant strides toward the goal of precision medicine.


Human papillomavirus and HPV vaccines: a review.
Cervical cancer, the most common cancer affecting women in developing countries, is caused by persistent infection with "high-risk" genotypes of human papillomaviruses (HPV). The most common oncogenic HPV genotypes are 16 and 18, causing approximately 70% of all cervical cancers. Types 6 and 11 do not contribute to the incidence of high-grade dysplasias (precancerous lesions) or cervical cancer, but do cause laryngeal papillomas and most genital warts. HPV is highly transmissible, with peak incidence soon after the onset of sexual activity. A quadrivalent (types 6, 11, 16 and 18) HPV vaccine has recently been licensed in several countries following the determination that it has an acceptable benefit/risk profile. In large phase III trials, the vaccine prevented 100% of moderate and severe precancerous cervical lesions associated with types 16 or 18 among women with no previous infection with these types. A bivalent (types 16 and 18) vaccine has also undergone extensive evaluation and been licensed in at least one country. Both vaccines are prepared from non-infectious, DNA-free virus-like particles produced by recombinant technology and combined with an adjuvant. With three doses administered, they induce high levels of serum antibodies in virtually all vaccinated individuals. In women who have no evidence of past or current infection with the HPV genotypes in the vaccine, both vaccines show > 90% protection against persistent HPV infection for up to 5 years after vaccination, which is the longest reported follow-up so far. Vaccinating at an age before females are exposed to HPV would have the greatest impact. Since HPV vaccines do not eliminate the risk of cervical cancer, cervical screening will still be required to minimize cancer incidence. Tiered pricing for HPV vaccines, innovative financing mechanisms and multidisciplinary partnerships will be essential in order for the vaccines to reach populations in greatest need.


Reduction of Fe(III), Mn(IV), and toxic metals at 100 degrees C by Pyrobaculum islandicum.
It has recently been noted that a diversity of hyperthermophilic microorganisms have the ability to reduce Fe(III) with hydrogen as the electron donor, but the reduction of Fe(III) or other metals by these organisms has not been previously examined in detail. When Pyrobaculum islandicum was grown at 100 degrees C in a medium with hydrogen as the electron donor and Fe(III)-citrate as the electron acceptor, the increase in cell numbers of P. islandicum per mole of Fe(III) reduced was found to be ca. 10-fold higher than previously reported. Poorly crystalline Fe(III) oxide could also serve as the electron acceptor for growth on hydrogen. The stoichiometry of hydrogen uptake and Fe(III) oxide reduction was consistent with the oxidation of 1 mol of hydrogen resulting in the reduction of 2 mol of Fe(III). The poorly crystalline Fe(III) oxide was reduced to extracellular magnetite. P. islandicum could not effectively reduce the crystalline Fe(III) oxide minerals goethite and hematite. In addition to using hydrogen as an electron donor for Fe(III) reduction, P. islandicum grew via Fe(III) reduction in media in which peptone and yeast extract served as potential electron donors. The closely related species P. aerophilum grew via Fe(III) reduction in a similar complex medium. Cell suspensions of P. islandicum reduced the following metals with hydrogen as the electron donor: U(VI), Tc(VII), Cr(VI), Co(III), and Mn(IV). The reduction of these metals was dependent upon the presence of cells and hydrogen. The metalloids arsenate and selenate were not reduced. U(VI) was reduced to the insoluble U(IV) mineral uraninite, which was extracellular. Tc(VII) was reduced to insoluble Tc(IV) or Tc(V). Cr(VI) was reduced to the less toxic, less soluble Cr(III). Co(III) was reduced to Co(II). Mn(IV) was reduced to Mn(II) with the formation of manganese carbonate. These results demonstrate that biological reduction may contribute to the speciation of metals in hydrothermal environments and could account for such phenomena as magnetite accumulation and the formation of uranium deposits at ca. 100 degrees C. Reduction of toxic metals with hyperthermophilic microorganisms or their enzymes might be applied to the remediation of metal-contaminated waters or waste streams.


Factors associated with patient-recalled smoking cessation advice in a low-income clinic.
It is recommended that providers advise cessation to their patients who smoke. However, patients' reports of cessation advice indicate disparities based on patients' race, gender, age, and smoking level. Providers' reports do not corroborate these disparities. We investigated whether smokers who receive their care in a community health center recalled their providers advising them to quit smoking when their providers documented such advice. We examined 219 patient-provider dyads to assess factors associated with lack of agreement between providers' documentation and patient recall. Patients were asked to recall any provider advice to quit smoking in the post 2 years. After every visit, providers completed a form to record the content of the visit. Most of the patients were African American, married, and uninsured. Sixty-eight percent of the dyads agreed in their documentation/recall. Patient race was the only factor associated with lack of agreement; African-American patients were more likely than white patients to provide discrepant reports. Although this study can not disentangle the racial difference in patient-provider recall/documentation, results may indicate an important area in which health disparities exist. Future studies should address the dynamics of patient-provider communication about smoking cessation, especially in populations that include ethnically diverse patients.


Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus.
The herpesvirus life cycle has two distinct phases: latency and lytic replication. The balance between these two phases is critical for viral pathogenesis. It is believed that cellular signals regulate the switch from latency to lytic replication. To systematically evaluate the cellular signals regulating this reactivation process in Kaposi sarcoma-associated herpesvirus, the effects of 26,000 full-length cDNA expression constructs on viral reactivation were individually assessed in primary effusion lymphoma-derived cells that harbor the latent virus. A group of diverse cellular signaling proteins were identified and validated in their effect of inducing viral lytic gene expression from the latent viral genome. The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. The same pathway also mediates spontaneous reactivation, which sets the first example to our knowledge of a specific cellular pathway being studied in the spontaneous reactivation process. Our study provides a functional genomic approach to systematically identify the cellular signals regulating the herpesvirus life cycle, thus facilitating better understanding of a fundamental issue in virology and identifying novel therapeutic targets.


Novel inositol phospholipid headgroup surrogate crystallized in the pleckstrin homology domain of protein kinase Balpha.
Protein kinase B (PKB/Akt) plays a key role in cell signaling. The PH domain of PKB binds phosphatidylinositol 3,4,5-trisphosphate translocating PKB to the plasma membrane for activation by 3-phosphoinositide-dependent protein kinase 1. The crystal structure of the headgroup inositol 1,3,4,5-tetrakisphosphate Ins(1,3,4,5)P4-PKB complex facilitates in silico ligand design. The novel achiral analogue benzene 1,2,3,4-tetrakisphosphate (Bz(1,2,3,4)P4) possesses phosphate regiochemistry different from that of Ins(1,3,4,5)P4 and surprisingly binds with similar affinity as the natural headgroup. Bz(1,2,3,4)P4 co-crystallizes with the PKBalpha PH domain in a fashion also predictable in silico. The 2-phosphate of Bz(1,2,3,4)P4 does not interact with any residue, and the D5-phosphate of Ins(1,3,4,5)P4 is not mimicked by Bz(1,2,3,4)P4. Bz(1,2,3,4)P4 is an example of a simple inositol phosphate surrogate crystallized in a protein, and this approach could be applied to design modulators of inositol polyphosphate binding proteins.