A Feasibility Trial of Power Up: Smartphone App to Support Patient Activation and Shared Decision Making for Mental Health in Young People.
Digital tools have the potential to support patient activation and shared decision making in the face of increasing levels of mental health problems in young people. There is a need for feasibility trials of digital interventions to determine the usage and acceptability of interventions. In addition, there is a need to determine the ability to recruit and retain research participants to plan rigorous effectiveness trials and, therefore, develop evidence-based recommendations for practice. This study aimed to determine the feasibility of undertaking a cluster randomized controlled trial to test the effectiveness of a smartphone app, Power Up, co-designed with young people to support patient activation and shared decision making for mental health. Overall, 270 young people were screened for participation and 52.5% (142/270) were recruited and completed baseline measures across 8 specialist child mental health services (n=62, mean age 14.66 (SD 1.99) year; 52% [32/62] female) and 2 mainstream secondary schools (n=80; mean age 16.88 [SD 0.68] years; 46% [37/80] female). Young people received Power Up in addition to management as usual or received management as usual only. Posttrial interviews were conducted with 11 young people from the intervention arms (specialist services n=6; schools n=5). Usage data showed that there were an estimated 50 (out of 64) users of Power Up in the intervention arms. Findings from the interviews indicated that young people found Power Up to be acceptable. Young people reported (1) their motivation for use of Power Up, (2) the impact of use, and (3) barriers to use. Out of the 142 recruited participants, 45.0% (64/142) completed follow-up measures, and the approaches to increase retention agreed by the steering group are discussed. The findings of this study indicate that the app is acceptable, and it is feasible to examine the effectiveness of Power Up in a prospective cluster randomized controlled trial. ClinicalTrials.gov NCT02552797; https://clinicaltrials.gov/ct2/show/NCT02552797 (Archived by WebCite at http://www.webcitation.org/6td6MINP0).


Blood-brain barrier and chemotherapeutic treatment of brain tumors.
The blood-brain barrier (BBB) is of pivotal importance to maintain homeostasis of the CNS, as it closely regulates the composition of the interstitial fluid in the brain. Unfortunately, malignancies that grow within the CNS may evade chemotherapeutic drugs using the same barrier, making this disease refractory to most chemotherapy regimens. This review will outline the impact of the BBB in brain cancer and discuss the efforts that have been made to enhance the drug exposure of brain tumors. Although this review will focus on the role of the BBB in primary brain cancer (malignant glioma), its impact on brain metastases will also be briefly discussed.


IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.
IL-17 mediates essential inflammatory responses in host defense and autoimmunity. The IL-17A-IL-17F signaling complex is composed of IL-17RA and IL-17RC, both of which are necessary for signal transduction. To date, the specific contribution of IL-17RC to downstream signaling remains poorly understood. To define the regions within the IL-17RC cytoplasmic tail required for signal transduction, we assayed signaling by a panel of IL-17RC deletion mutants. These findings reveal that IL-17RC inducibly associates with a specific glycosylated IL-17RA isoform, in a manner independent of the IL-17RC cytoplasmic tail. Using expression of the IL-17 target genes IL-6 and 24p3/lipocalin-2 as a readout, functional reconstitution of signaling in IL-17RC(-/-) fibroblasts required the SEF/IL-17R signaling domain (SEFIR), a conserved motif common to IL-17R family members. Unexpectedly, the IL-17RC SEFIR alone was not sufficient to reconstitute IL-17-dependent signaling. Rather, an additional sequence downstream of the SEFIR was also necessary. We further found that IL-17RC interacts directly with the adaptor/E3 ubiquitin ligase Act1, and that the functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1. Finally, we show that IL-17RC is required for in vivo IL-17-dependent responses during oral mucosal infections caused by the human commensal fungus Candida albicans. These results indicate that IL-17RC is vital for IL-17-dependent signaling both in vitro and in vivo. Insight into the mechanisms by which IL-17RC signals helps shed light on IL-17-dependent inflammatory responses and may ultimately provide an avenue for therapeutic intervention in IL-17-mediated diseases.


Vaginal progesterone for preterm birth prevention in women with arrested preterm labor.
We tested the hypothesis that administration of vaginal progesterone in women with arrested preterm labor would result in lower rates of preterm birth <37 weeks compared to placebo. We performed a randomized, placebo-controlled trial comparing vaginal progesterone to placebo in women with arrested preterm labor. Our trial included women with a singleton or twin gestation at 240/7-336/7 weeks' gestation who presented with preterm labor with cervical dilation ≥1 centimeter but remained undelivered. Participants were randomized to receive vaginal progesterone 200 mg daily or an identical placebo. The primary outcome was preterm birth <37 weeks. We performed an updated systematic review and meta-analysis of clinical trials, including our results. We searched MEDLINE, EMBASE, CINHAL, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov using the key terms to identify relevant trials. The risk of bias was appraised using the Cochrane risk-of-bias tool. Data were synthesized using random-effects models. Heterogeneity was assessed using Higgins I2. The randomized trial was prematurely terminated due to slow recruitment. There were 18 women randomized to receive vaginal progesterone who had complete follow-up data and 18 women in the placebo group. The risk of preterm birth <37 weeks was not significantly different in the groups (RR 1.10, 95% CI 0.63-1.19). Secondary outcomes were also similar. Thirteen trials with 1658 women (835 in the vaginal progesterone and 823 in the control groups) were included in the meta-analysis. Risk of preterm birth <37 weeks was similar in women who received progesterone and those in the control group (pooled RR 1.06, 95% CI 0.83-1.35). Latency was significantly longer among women with arrested preterm labor who received vaginal progesterone (weighted mean difference: 9.2 d, 95% CI 3.2-15.1), but further analysis showed that prolonged latency was only observed in the subgroup of studies that were not placebo-controlled. This randomized controlled trial and meta-analysis do not support the use of vaginal progesterone for the prevention of preterm birth in women who present in preterm labor.


Rituximab therapy for Type I membranoproliferative glomerulonephritis.
Type I membranoproliferative glomerulonephritis (MPGN) is an immune-complex disease with a relatively poor prognosis. It has no established treatment in adults. Our hypothesis was that this disease would respond to B cell depletion with rituximab, an anti-CD20 monoclonal antibody. We conducted an openlabel trial, in Canada and the United States, of rituximab in 6 adult patients with Type I MPGN (4 idiopathic, 2 with cryoglobulinemia). The rituximab dose was 1,000 mg intravenously on Day 1 and on Day 15. The patients were followed for 1 year. The primary outcome was the change in proteinuria. Peripheral blood B cells were suppressed, after rituximab, in all patients. The mean urinary protein excretion was 3.9 ± 2.0 g/d before treatment. Proteinuria fell in all patients, at all-time points, after rituximab administration. The difference was statistically significant (p < 0.05) at 6, 9 and 12 months, but not at 3 months. The minimum mean urinary protein excretion was 1.4 ± 1.4 g/d at 9 months. There were 2 complete and 3 partial remissions among the 6 patients. The creatinine clearance did not change significantly over the course of the study. There were no adverse effects. Rituximab reduced proteinuria among patients with Type I MPGN. This trial suggests that B cells may play a role in this disease and that additional study of B-cell suppression is warranted.


Temperament Predicts the Quality of Social Interactions in Captive Female Rhesus Macaques (Macaca mulatta).
Previous reports suggest that female macaques with greater similarity in emotionality and nervous temperament, as evaluated in a well-established BioBehavioral Assessment (BBA) at the California National Primate Research Center, were more likely to form successful pairs. We tested whether the same measures can also predict the quality of social interactions among 20 female rhesus macaque pairs. We correlated the pairs' emotionality and nervous temperament scores obtained in infancy and the levels of behaviors recorded systematically during the pairing process years later. Supporting previous findings, partners with similar emotionality scores were more affiliative, and pairs with similar nervous temperament expressed less dominance/submissive behavior. Exploratorily, we found that pairs that were better at processing social information (part of BBA) were also more anxious. Such animals should be prioritized to be introduced in rooms that house calmer, less aggressive animals and provide opportunities for hiding to alleviate their anxiety. Indeed, positive social experiences not only promote animal welfare, but also reduce stress related confounds and unexplained data variability. Therefore, by incorporating the animals' temperament into the pair configuration process we increase the likelihood of forming high-quality pairs, both in terms of welfare and the research of which they are a part.


The assessment of analogical thinking modifiability among regular, special education, disadvantaged, and mentally retarded children.
The objectives of the current study were (a) to develop a measure of children's analogical thinking modifiability (CATM) based on the Feuerstein, Rand, and Hoffman (1979) theory of dynamic assessment of cognitive modifiability, (b) to compare the performance of groups assumed to be differentially modified by intervention, (c) to compare CATM performance with performance on a conventional test, and (d) to study qualitative changes after a learning process. Subjects were disadvantaged, regular, and special education kindergarten children (N = 140), and mentally retarded children (N = 20). The CATM was administered together with the Ravens Colored Progressive Matrices (RCPM) in a balanced order. Disadvantaged and regular children achieved higher gain scores than other groups in both none-or-all and partial credit methods (p less than .01). The MR and the special education groups showed small gains according to the none-or-all credit method; however, according to the partial credit method, the MR group showed high gains and the special education group a performance decrease. Performance scores on the CATM were higher than on the RCPM, especially in comparison to the B8-B12 items--differences reach a peak of 61% and 67% for the disadvantaged and regular groups, respectively. Qualitative analysis indicated that form mistakes were most resistant to change, whereas color mistakes were most easy to modify. Results were explained within Feuerstein's theoretical framework of cognitive modifiability. Impaired cognitive functions as well as analytic versus synthetic processes were suggested to explain group differences.


Variations in Definitions and Outcome Measures in Gastroesophageal Reflux Disease: A Systematic Review.
Gastroesophageal reflux (GER) is defined as GER disease (GERD) when it leads to troublesome symptoms and/or complications. We hypothesized that definitions and outcome measures in randomized controlled trials (RCTs) on pediatric GERD would be heterogeneous. Systematically assess definitions and outcome measures in RCTs in this population. Data were obtained through Cochrane, Embase, Medline, and Pubmed databases. We selected English-written therapeutic RCTs concerning GERD in children 0 to 18 years old. Data were tabulated and presented descriptively. Each individual parameter or set of parameters with unique criteria for interpretation was considered a single definition for GER(D). Quality was assessed by using the Delphi score. A total of 2410 unique articles were found; 46 articles were included. Twenty-six (57%) studies defined GER by using 25 different definitions and investigated 25 different interventions. GERD was defined in 21 (46%) studies, all using a unique definition and investigating a total of 23 interventions. Respectively 87 and 61 different primary outcome measures were reported by the studies in GER and GERD. Eight (17%) studies did not report on side effects. Of the remaining 38 (83%) studies that did report on side effects, 18 (47%) included this as predefined outcome measure of which 4 (22%) as a primary outcome measure. Sixteen studies (35%) were of good methodological quality. Only English-written studies were included. Inconsistency and heterogeneity exist in definitions and outcome measures used in RCTs on pediatric GER and GERD; therefore, we recommend the development of a core outcome set.


Platelet abnormalities in Huntington's disease.
Huntington's disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood-brain barrier (BBB) leakage. Seeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells. We assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model. Our findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis. Taken together, our results provide a better understanding for the impact of mHtt on platelet function.


Dot scissor: a single-click interface for mesh segmentation.
This paper presents a very easy-to-use interactive tool, which we call dot scissor, for mesh segmentation. The user's effort is reduced to placing only a single click where a cut is desired. Such a simple interface is made possible by a directional search strategy supported by a concavity-aware harmonic field and a robust voting scheme that selects the best isoline as the cut. With a concavity-aware weighting scheme, the harmonic fields gather dense isolines along concave regions which are natural boundaries of semantic components. The voting scheme relies on an isoline-face scoring mechanism that considers both shape geometry and user intent. We show by extensive experiments and quantitative analysis that our tool advances the state-of-the-art segmentation methods in both simplicity of use and segmentation quality.


Orthostatic tolerance, cerebral oxygenation, and blood velocity in humans with sympathetic failure.
Patients with orthostatic hypotension due to sympathetic failure become symptomatic when standing, although their capability to maintain cerebral blood flow is reported to be preserved. We tested the hypothesis that in patients with sympathetic failure, orthostatic symptoms reflect reduced cerebral perfusion with insufficient oxygen supply. This study addressed the relationship between orthostatic tolerance, mean cerebral artery blood velocity (V(mean), determined by transcranial Doppler ultrasonography), oxygenation (oxyhemoglobin [O(2)Hb], determined by near-infrared spectroscopy), and mean arterial pressure at brain level (MAP(MCA), determined by finger arterial pressure monitoring [Finapres]) in 9 patients (aged 37 to 70 years; 4 women) and their age- and sex-matched controls during 5 minutes of standing. Supine MAP(MCA) (108+/-14 versus 86+/-14 mm Hg) and V(mean) (84+/-21 versus 62+/-13 cm. s(-1)) were higher in the patients. After 5 minutes of standing, MAP(MCA) was lower in the patients (31+/-14 versus 72+/-14 mm Hg), as was V(mean) (51+/-8 versus 59+/-9 cm. s(-1)), with a larger reduction in O(2)Hb (-11. 6+/-4 versus -6.7+/-4.5 micromol. L(-1)). Four patients terminated standing after 1 to 3.5 minutes. In these symptomatic patients, the orthostatic fall in V(mean) was greater (45+/-6 versus 64+/-10 cm. s(-1)), and the orthostatic decrease in O(2)Hb (-12.0+/-3.3 versus -7.6+/-3.9 micromol. L(-1)) tended to be larger. The reduction in MAP(MCA) was larger after 10 seconds of standing, and MAP(MCA) was lower after 1 minute (25+/-8 versus 40+/-6 mm Hg). In patients with sympathetic failure, the orthostatic reduction in cerebral blood velocity and oxygenation is larger. Patients who become symptomatic within 5 minutes of standing are characterized by a pronounced orthostatic fall in blood pressure, cerebral blood velocity, and oxygenation manifest within the first 10 seconds of standing.


Topological properties of bovine papillomavirus type 1 (BPV-1) DNA in episomal nucleoprotein complexes: a model system for chromatin organization in higher eukaryotes.
Sedimentation analysis of isolated episomal bovine papillomavirus type 1 (BPV-1) nucleoprotein complexes in sucrose gradients and subsequent separation of the purified DNA in chloroquine gels revealed different classes of molecules, varying in their degree of superhelicity. Since torsionally stressed DNA favors the adoption of secondary structures, we employed the single-strand-specific S1 nuclease to detect such structural alterations in both naked DNA and native chromatin. Direct examination of nuclease digestion products in chloroquine gels showed that neither the naked DNA nor the BPV-1 nucleoprotein complexes in isolated nuclei were cleaved randomly by the enzyme. Instead, there was a strict dependence on nuclease susceptibility and the degree of supercoiling, strongly suggesting that the structural features detected by S1 nuclease are due to the occurrence of torsionally stressed viral chromatin. Mapping analysis using the indirect end-labeling method demonstrated an S1-nuclease cleavage site adjacent to 20 homopurine residues known to be hypersensitive to S1 attack. Furthermore, direct methylation experiments with viral chromatin in isolated nuclei indicated that only circular, covalently closed nucleoprotein complexes served as substrate, whereas linearized BPV-1 chromatin was not susceptible to exogenously added Hhal methylase. This observation raises the possibility that the modulation of topology in nucleosomally organized DNA might also play a role in eukaryotic DNA methylation.


Sturgeon conservation genomics: SNP discovery and validation using RAD sequencing.
Caviar-producing sturgeons belonging to the genus Acipenser are considered to be one of the most endangered species groups in the world. Continued overfishing in spite of increasing legislation, zero catch quotas and extensive aquaculture production have led to the collapse of wild stocks across Europe and Asia. The evolutionary relationships among Adriatic, Russian, Persian and Siberian sturgeons are complex because of past introgression events and remain poorly understood. Conservation management, traceability and enforcement suffer a lack of appropriate DNA markers for the genetic identification of sturgeon at the species, population and individual level. This study employed RAD sequencing to discover and characterize single nucleotide polymorphism (SNP) DNA markers for use in sturgeon conservation in these four tetraploid species over three biological levels, using a single sequencing lane. Four population meta-samples and eight individual samples from one family were barcoded separately before sequencing. Analysis of 14.4 Gb of paired-end RAD data focused on the identification of SNPs in the paired-end contig, with subsequent in silico and empirical validation of candidate markers. Thousands of putatively informative markers were identified including, for the first time, SNPs that show population-wide differentiation between Russian and Persian sturgeons, representing an important advance in our ability to manage these cryptic species. The results highlight the challenges of genotyping-by-sequencing in polyploid taxa, while establishing the potential genetic resources for developing a new range of caviar traceability and enforcement tools.


Early treatment of anterior open bite: Comparison of the vertical and horizontal morphological changes induced by magnetic bite-blocks and adjusted rapid molar intruders.
This prospective clinical study aims to determine the differences between two treatment modalities for anterior open bite in growing patients. The treatment modalities involved the use of magnetic bite-blocks (MBBs) or rapid molar intruders (RMIs) applied with posterior bite-blocks. Fifteen consecutive patients with a mean age of 11.2 (standard deviation [SD] = 1.6) years and a mean open bite of -3.9 mm were treated with MBBs. Another 15 consecutive patients with a mean age of 10.9 (SD = 1.8) years and a mean open bite of -3.8 mm were treated with RMIs applied on bite-blocks. Cephalometric radiographs were obtained before (T1) and immediately after appliance removal (T2). The treatments lasted four months, during which the appliances were cemented to the teeth. The morphological changes were measured in each group and compared using logistic regression analysis. The MBB group exhibited significantly greater decreases in SNA angle, ANB angle, overjet, and maxillary incisor angle (p < 0.05). The MBBs induced greater effects on the maxilla and maxillary dentition. The MBBs restrained maxillary forward growth and retracted the maxillary incisors more effectively than did the RMIs. Consequently, changes in the intermaxillary relationships and overjets were more distinct in the MBB group. The anteroposterior differences between the appliances suggest that MBBs should be preferred for the treatment of patients with Class II open bites and maxillary incisor protrusions.


Nanoscale co-organization of quantum dots and conjugated polymers using polymeric micelles as templates.
Hierarchical organization of light-absorbing molecules is integral to natural light harvesting complexes and has been mimicked by elegant chemical systems. A challenge is to attain such spatial organization among nanoscale systems. Interactions between nanoscale systems, e.g., conjugated polymers, carbon nanotubes, quantum dots, and so on, are of interest for basic and applied reasons. However, typically the excited-state interactions and dynamics are examined in rather complex blends, such as cast films. A model system with complexity intermediate between a film and a supramolecular system would yield helpful insights into electronic energy and charge transfer. Here, we report a simple and versatile approach to achieving spatially defined organization of colloidal CdSe, CdSe/ZnS core/shell, or PbS nanocrystals (quantum dots) with poly(3-hexylthiophenes) (P3HTs) using micelles of poly(styrene-b-4-vinylpyridine) (PS-b-P4VP) as the main structural motif. We compare the characteristics of this system to those of natural light-harvesting complexes. Bulk heterojunction films (and related systems) are characterized by electronic interactions, and therefore dynamics of charge and energy transfer, at interfaces rather than between specific donor-acceptor molecules. Owing to structural disorder, such systems are inherently complex. Therefore, we expect that the spatially defined organization of the active components in the present system provides new opportunities for studying the complicated photophysics intrinsic to blends of nanoscale systems, such as bulk heterojunctions by establishing simplified and better controlled interfaces.


Synthesis of guanidinium-modified hyaluronic Acid hydrogel.
In this report, a new guanidinylating reagent is presented, which was developed without any protection/deprotection strategy and was successfully employed for linking to hyaluronan in aqueous solution. The dually functionalised HA biopolymer bearing guanidinium and hydrazide groups was synthesised to form hydrogel in less than a minute when mixed with aldehyde-modified HA. This hydrogel exhibited higher storage modulus with enhanced stability in PBS when compared to the non-guanidine-containing gel. The gel shift assay showed that this biopolymer formed a stable complex with DNA as well as efficient gene transfection to cells that express HA-receptor CD44. The toxicity studies of this polymer with fibroblast cells revealed that the cells were almost 80% viable after 4 d of incubation at high HA concentration (2.5 × 10(-3) M).


A photobiological evaluation of tanning booths.
The use of tanning booths as a substitute for natural sunlight is becoming increasingly popular. However, unless careful attention is paid to proper design and maintenance, the radiation field inside a tanning booth can be highly anisotropic. The use of simple, inexpensive ultraviolet radiation meters to measure dosage can lead to serious overexposure. Since the ultraviolet radiation inside a tanning booth has a greater proportion of short wavelengths (less than 300 nanometers) than natural sunlight, the amount of skin cancer-inducing radiation received for a tan may be twice that received for a natural suntan.


Single-ion magnetic anisotropy and isotropic magnetic couplings in the metal-organic framework Fe2(dobdc).
The metal-organic framework Fe2(dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate), often referred to as Fe-MOF-74, possesses many interesting properties such as a high selectivity in olefin/paraffin separations. This compound contains open-shell Fe(II) ions with open coordination sites which may have large single-ion magnetic anisotropies, as well as isotropic couplings between the nearest and next nearest neighbor magnetic sites. To complement a previous analysis of experimental data made by considering only isotropic couplings [Bloch et al. Science 2012, 335, 1606], the magnitude of the main magnetic interactions are here assessed with quantum chemical calculations performed on a finite size cluster. It is shown that the single-ion anisotropy is governed by same-spin spin-orbit interactions (i.e., weak crystal-field regime), and that this effect is not negligible compared to the nearest neighbor isotropic couplings. Additional magnetic data reveal a metamagnetic behavior at low temperature. This effect can be attributed to various microscopic interactions, and the most probable scenarios are discussed.


α-Synuclein expression selectively affects tumorigenesis in mice modeling Parkinson's disease.
Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn-dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over-expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer.


Behavioral profiles of children with infantile nephropathic cystinosis.
Children with infantile nephropathic cystinosis have evidence of visuospatial and arithmetic deficits on a background of normal intellectual and verbal skills. This study aimed to define further their behavioral phenotype. The Achenbach Child Behavior Checklist was completed by parents of: 64 children and adolescents with cystinosis (33 females, 31 males; mean age 8 y 8 mo, range 4 to 16y, SD 2 y 11 mo); 101 healthy controls (47 females, 54 males; mean age 8 y 4 mo, range 4 to 16 y, SD 2 y 11 mo); 21 children and adolescents with cystic fibrosis (CF), termed chronic-disease controls (9 females, 12 males; mean age 11 y 3 mo, age range 4 to 17 y, SD 3 y 5 mo). Compared with healthy controls, individuals with cystinosis had evidence of a significantly higher incidence of behavioral problems, including social problems, somatic complaints, and attention problems. Compared with the chronic-disease control group, the cystinosis group differed only on the Social Problems scale, with 22% of participants with cystinosis scoring in the 'at risk' range whereas no participant with CF received an elevated score on this scale. We conclude that children and adolescents with cystinosis have evidence of a significant incidence of social difficulties compared with individuals with another chronic illness and healthy participants. The combination of visuospatial problems, difficulty with arithmetic, attention problems, and social difficulties seen in the cystinosis group constitutes a behavioral phenotype of this genetic disorder. This cluster of cognitive and behavioral symptoms is also seen in the nonverbal learning disabilities syndrome, and suggests a possible early difference in brain development in children with cystinosis compared with children who do not share this genetic disorder.


Mini-UAV based sensory system for measuring environmental variables in greenhouses.
This paper describes the design, construction and validation of a mobile sensory platform for greenhouse monitoring. The complete system consists of a sensory system on board a small quadrotor (i.e., a four rotor mini-UAV). The goals of this system include taking measures of temperature, humidity, luminosity and CO2 concentration and plotting maps of these variables. These features could potentially allow for climate control, crop monitoring or failure detection (e.g., a break in a plastic cover). The sensors have been selected by considering the climate and plant growth models and the requirements for their integration onboard the quadrotor. The sensors layout and placement have been determined through a study of quadrotor aerodynamics and the influence of the airflows from its rotors. All components of the system have been developed, integrated and tested through a set of field experiments in a real greenhouse. The primary contributions of this paper are the validation of the quadrotor as a platform for measuring environmental variables and the determination of the optimal location of sensors on a quadrotor.


Bartonella spp. Bloodstream Infection in a Canadian Family.
Historically, Bartonella spp. have been associated with febrile illness (Oroya fever, trench fever, and cat scratch disease), endocarditis (numerous Bartonella spp.), and vasoproliferative lesions (Bartonella bacilliformis, Bartonella quintana, Bartonella henselae, and Bartonella vinsonii subsp. berkhoffii), occurring most often but not exclusively in immunocompromised patients. Recently, bloodstream infections with various Bartonella spp. have been documented in nonimmunocompromised individuals in association with a spectrum of cardiovascular, neurologic, and rheumatologic symptoms. As documented in this family, symptoms for which the medical implications remain unclear can occur in multiple family members infected with one or more Bartonella spp. Serial serologic and molecular microbiological findings supported exposure to or infection with Bartonella spp. in all seven family members. Either antibiotics failed to eliminate bacteremic infection, resulted in partial resolution of symptoms, or potentially reinfection occurred during the 19-month study period. There is a substantial need for clinical research to clarify the extent to which Bartonella spp. bacteremia induces nonspecific cardiovascular, neurologic, or rheumatologic symptoms, for ongoing improvement in the sensitivity and specificity of diagnostic testing, and clarification as to if, when, and how to treat patients with documented Bartonella spp. bacteremia.


[The social transformations observed in a family with retarded children].
A deep educational work was carried out with a family presenting generalized retardation in most of its members, with very deficient socioeconomic and hygiene conditions and a child with retardation of organic cause, main point of disorders occurring at his home and neighborhood. Transformations were reached in this family by means of field visits, specialized medical care and the aid of the community revolutionary masses; life level was improved, reaching a higher development of all its members who were incorporated to social life. Valuable benefit rendered by social medicine and importance of the new model of primary care to the family, and within such model main role played by the nurse, as well as the aid given by the community mass organizations, was demonstrated.


Evaluating the effectiveness of care coordination interventions designed and implemented through a participatory action research process: Lessons learned from a quasi-experimental study in public healthcare networks in Latin America.
Despite increasing recommendations for health professionals to participate in intervention design and implementation to effect changes in clinical practice, little is known about this strategy's effectiveness. This study analyses the effectiveness of interventions designed and implemented through participatory action research (PAR) processes in healthcare networks of Brazil, Chile, Colombia, Mexico and Uruguay to improve clinical coordination across care levels, and offers recommendations for future research. The study was quasi-experimental. Two comparable networks, one intervention (IN) and one control (CN), were selected in each country. Baseline (2015) and evaluation (2017) surveys of a sample of primary and secondary care doctors (174 doctors/network/year) were conducted using the COORDENA® questionnaire. Most of the interventions chosen were based on joint meetings, promoting cross-level clinical agreement and communication for patient follow-up. Outcome variables were: a) intermediate: interactional and organizational factors; b) distal: experience of cross-level clinical information coordination, of clinical management coordination and general perception of coordination between levels. Poisson regression models were estimated. A statistically significant increase in some of the interactional factors (intermediate outcomes) -knowing each other personally and mutual trust- was observed in Brazil and Chile INs; and in some organizational factors -institutional support- in Colombia and Mexico. Compared to CNs in 2017, INs of Brazil, Chile, Colombia and Mexico showed significant differences in some factors. In distal outcomes, care consistency items improved in Brazil, Colombia and Uruguay INs; and patient follow-up improved in Chile and Mexico. General perception of clinical coordination increased in Brazil, Colombia and Mexico INs. Compared to CNs in 2017, only Brazil showed significant differences. Although more research is needed, results show that PAR-based interventions improved some outcomes regarding clinical coordination at network level, with differences between countries. However, a PAR process is, by definition, slow and gradual, and longer implementation periods are needed to achieve greater penetration and quantifiable changes. The participatory and flexible nature of interventions developed through PAR processes poses methodological challenges (such as defining outcomes or allocating individuals to different groups in advance), and requires a comprehensive mixed-methods approach that simultaneously evaluates effectiveness and the implementation process to better understand its outcomes.


Interlayer-expanded molybdenum disulfide nanocomposites for electrochemical magnesium storage.
Mg rechargeable batteries (MgRBs) represent a safe and high-energy battery technology but suffer from the lack of suitable cathode materials due to the slow solid-state diffusion of the highly polarizing divalent Mg ion. Previous methods improve performance at the cost of incompatibility with anode/electrolyte and drastic decrease in volumetric energy density. Herein we report interlayer expansion as a general and effective atomic-level lattice engineering approach to transform inactive intercalation hosts into efficient Mg storage materials without introducing adverse side effects. As a proof-of-concept we have combined theory, synthesis, electrochemical measurement, and kinetic analysis to improve Mg diffusion behavior in MoS2, which is a poor Mg transporting material in its pristine form. First-principles simulations suggest that expanded interlayer spacing allows for fast Mg diffusion because of weakened Mg-host interactions. Experimentally, the expansion was realized by inserting a controlled amount of poly(ethylene oxide) into the lattice of MoS2 to increase the interlayer distance from 0.62 nm to up to 1.45 nm. The expansion boosts Mg diffusivity by 2 orders of magnitude, effectively enabling the otherwise barely active MoS2 to approach its theoretical storage capacity as well as to achieve one of the highest rate capabilities among Mg-intercalation materials. The interlayer expansion approach can be leveraged to a wide range of host materials for the storage of various ions, leading to novel intercalation chemistry and opening up new opportunities for the development of advanced materials for next-generation energy storage.


HIV prevention for Black women: structural barriers and opportunities.
Black women bear a disproportionate burden of HIV/AIDS in North America. The purpose of this investigation was to explore Black Canadian women's perspectives on HIV risk and prevention. Four 90-minute focus groups (n=26) and six key informant interviews were conducted in Toronto with Black women of African and Caribbean descent and low socioeconomic status. Data analysis revealed a number of potent barriers to existing HIV preventive interventions: stigma, cultural disconnections, lack of engagement of Black religious institutions, and multiple intersecting forms of discrimination. Recommended HIV prevention opportunities included the Black church, mainstreaming, health care providers, and ethno-specific agencies. HIV prevention strategies for North American Black women, rather than focusing on HIV and individual risk behaviors, may benefit from a primary focus on social and structural factors (e.g., promoting gender equality, economic opportunity, women-controlled prevention technologies and combating racism in health care) thereby integrating HIV prevention into the larger context of community health and survival.


Estradiol inhibits allograft-inducible major histocompatibility complex class II antigen expression and transplant arteriosclerosis in the absence of immunosuppression.
The etiology of transplant arteriosclerosis is unknown, but current data point to the alloimmune response. Previously, we found that estradiol-17beta (E2) with immunosuppressant cyclosporine abolishes major histocompatibility complex (MHC) class II expression in the allograft. This study determines the effect of E2 on MHC class II antigen expression in the allograft, in the absence of immunosuppression. Lewis male rats received orthotopic abdominal aorta allografts from male Brown-Norway rats. The recipients were treated continuously subcutaneously with either 20 microg x kg(-1) x day1 of E2 (n=20) or placebo (n=20), from 2 days before transplantation until death on posttransplant days 1, 3, 7, and 14. The allografts were harvested and processed for morphometry and for immunohistochemical staining of MHC class II antigens, macrophages, CD4 and CD8 T lymphocytes, interferon-gamma (IFN-gamma), and IFN-gamma receptor. With E2 treatment, we observed that inducible MHC class II antigen expression is abolished in the media of the vascular allograft; the expression of IFN-gamma and IFN-gamma receptor is unaffected; and macrophage infiltration of the vascular allograft is inhibited significantly (P<0.01), whereas the CD4 and CD8 T lymphocytes are not significantly (P=0.07) suppressed. The myointimal hyperplasia in the allografts from E2-treated-recipients was 3-4-fold less than that from the placebo-treated recipients. Without immunosuppression, E2 inhibition of transplant arteriosclerosis is still associated with inhibition of inducible MHC class II antigen expression in the allografts. The estradiol-17beta abolition of inducible MHC class II antigen expression in the aorta allograft occurs in spite of up-regulation of IFN-gamma ligand and receptor protein.


The effect of isoflurane on neuronal necrosis following near-complete forebrain ischemia in the rat.
The effect of deep isoflurane anesthesia on ischemically induced neuronal damage was evaluated in the rat. Sixteen mechanically ventilated animals were maintained normocapnic and normothermic while subjected to a near complete forebrain ischemia insult induced with systemic hypotension (MAP = 50 +/- mmHg) and bilateral carotid artery occlusion. Prior to ischemia, eight of the rats received isoflurane by inhalation until the EEG demonstrated a burst suppression pattern; the other eight were untreated controls. After 10 min of ischemia, the carotid clamps were removed, blood pressure was restored, and, in the treated group, isoflurane administration discontinued. Following the ischemic insult, the animals were observed over a 7-day period, at which time they were killed and the brains prepared for histologic study. Severity of damage was assessed by a direct count of irreversibly damaged neurons, which appear bright red when stained with cresyl violet-acid fuchsin. Areas of particular interest were those that characteristically display vulnerability to ischemic damage, i.e., hippocampus, caudate nuclei, and neocortex. The control group revealed severe damage in the hippocampal CA1 sector (70% cells acidophilic) with more variability in the caudate nuclei and neocortex. The treated group showed a similar extent of damage with approximately 74% cells acidophilic in hippocampus (CA1). Clinical appearance was indistinguishable between groups. The authors conclude that pretreatment with isoflurane shows no beneficial effects on delayed neuronal necrosis following near-complete forebrain ischemia.


Autoimmunity and ALS.
Significant evidence has accrued suggesting that antibodies to voltage-gated calcium channel are observed in at least some patients with sporadic ALS (SALS) and that such antibodies alter the function of these ion channels in vitro and in vivo. Further, passive transfer of these immunoglobulin-containing fractions into mice produces changes at the neuromuscular junction that are very similar to changes observed in patients with SALS. These changes reflect local alterations in intracellular Ca2+ homeostasis and, in animal models, may also evidence early changes of motoneuron injury, such as Golgi apparatus swelling and fragmentation. Although not yet documented to induce motoneuron death in vivo, SALS immunoglobulins induce Ca(2+)-dependent apoptosis in a differentiated motoneuron hybrid cell line via a mechanism that involves oxidative injury. SALS immunoglobulin-mediated apoptosis in these cells is regulated by the presence of the same calcium-binding proteins that may modulate selective motoneuron vulnerability in SALS.


Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers.
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology.


A Case of Linear Hypertrophic Lichen Planus in a Pediatric Patient.
Lichen planus (LP) is a chronic inflammatory disease of the skin and mucosa. Of the various types, the hypertrophic type is characterized by thickened, purplish hyperkeratotic plaques and nodules. The course of hypertrophic LP tends to be more chronic than those of other types. A 12-year-old girl presented with a 2-year history of warty papules and plaques in a zosteriform configuration along one flank. Histopathology revealed hyperkeratosis and papillomatosis with wedge-shaped hypergranulosis. A lichenoid lymphocytic infiltrate with vacuolar change in the basal layer was evident. She was prescribed oral doxycycline, a topical corticosteroid, and tacrolimus. After 7 weeks, the skin lesions became significantly flattened and faded. LP is less common but more severe in children than in adults. The unilateral, linear hypertrophic type of LP is uncommon. Herein, we report a rare case of linear hypertrophic LP in a child.


Percutaneous transluminal angioplasty for suspected vertebral artery stump syndrome.
Vertebral artery stump syndrome is a rare disease associated with a posterior circulation stroke after vertebral artery origin occlusion. However, few reports have addressed its management. We herein present a case involving a patient with vertebral artery stump syndrome who underwent successful intravascular intervention. We also present a literature review of previous cases of this rare disease. The present case involved a 91-year-old man with acute onset of vertigo and disturbance of consciousness. Diffusion-weighted imaging showed an acute ischaemic stroke in the bilateral cerebellar hemispheres. Magnetic resonance angiography revealed left vertebral artery origin occlusion. Angiography detected a nearly occluded left vertebral artery site, with distal antegrade collateral flow via the deep cervical artery at the C6 level. We observed intravascular stasis at the proximal end of the left vertebral artery via the collateral flow. We performed percutaneous transluminal angioplasty towards the occluded left vertebral artery site. The flow from the left vertebral artery was significantly improved. This is the first report of percutaneous transluminal angioplasty performed for vertebral artery stump syndrome. Although vertebral artery stump syndrome has a high risk of recurrence and a poor prognosis, endovascular intervention showed a better outcome than pharmacotherapy in our patient. However, such cases are rare and further investigations are needed.


Adrenalectomy in the ferret.
A simple adrenalectomy technique is presented for the ferret (Mustela putorius furo). The adrenal glands were removed in two operations with an interim recovery period of approximately 1 week. The right adrenal should be removed first, as the surgery is complicated on that side by fascia which binds the adrenal to the inferior vena cava. Salt solution (1% NaCl) in place of water will maintain sodium balance.


MyD88 in DNA repair and cancer cell resistance to genotoxic drugs.
MyD88 is an adaptor molecule in Toll-like receptor and interleukin 1 receptor signaling implicated in tumorigenesis through proinflammatory mechanisms. We have recently reported that MyD88 also directly promotes optimal activation of the Ras/Erk pathway. Here we investigate MyD88 implication in the maintenance of the transformation of Ras-dependent tumors. RNA interference was used to inhibit MyD88 expression in the colon cancer cell lines HCT116 and LS513. Apoptosis, DNA damage, p53 function, ERCC1 levels, and Ras and inflammatory signaling pathways were analyzed. Using in vitro assays and xenotransplantation in nude mice (five per group), HCT116 tumor growth was assessed following MyD88 knockdown in presence or absence of chemotherapy. MyD88 exerts antiapoptotic functions in colon cancer cells via the Ras/Erk, but not the NF-κB, pathway. MyD88 inhibition leads to defective ERCC1-dependent DNA repair and to accumulation of DNA damage, resulting in cancer cell death via p53. Furthermore, we show that knocking down MyD88 sensitizes cancer cells to genotoxic agents such as platinum salts in vitro and in vivo. Indeed, HCT116 tumor growth following treatment with a combination of suboptimal MyD88 inhibition and suboptimal doses of cisplatin (fold tumor increase = 5.4 ± 1.6) was statistically significantly reduced in comparison to treatment with doxycycline alone (12.4 ± 3.1) or with cisplatin alone (12.5 ± 2.6) (P = .005 for both, one-sided Student t test). Collectively, these results indicate a novel and original link between inflammation, DNA repair, and cancer, and provide further rationale for MyD88 as a potential therapeutic target in Ras-dependent cancers, in the context of concomitant genotoxic chemotherapy.


[Specific growth rate and macrophagal infiltration of experimental tumors].
The relationship between the macrophage infiltration and the specific growth rate of tumours was studied by the technique of spontaneous migration of lymphoreticular cells from tissue fragments. In the case of dimethylnitrosamine-induced rat kidney tumours and Ehrlich solid tumour in mice the increased migration of activated macrophages was associated with the average specific growth rate. The macrophage infiltration of tumours and systemic immune reactivity to tumour-associated antigens depend probably on tumour cell kinetics.


Does Breast Implant-Associated ALCL Begin as a Lymphoproliferative Disorder?
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has been included as a provisional entity in the revised version of the World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissue. To increase opportunities to intervene with early diagnosis, treatment, and possible prevention, it is important to consider that BIA-ALCL may evolve from a preexisting lymphoproliferative disorder characterized by (1) an indolent localized (in situ) disease in approximately 80 percent of reported cases; (2) a requirement for external cytokine stimulation for cell survival; (3) CD30 cells in some clinically benign seromas/capsules; (4) undetected T-cell clonality in some cases; (5) JAK/STAT mutations in only a minority of cases; and (6) cure by capsulectomy and implant removal in most cases. BIA-ALCL resembles CD30 cutaneous lymphoproliferative disorder: ALK, CD30 anaplastic cells with an aberrant T-cell phenotype; overexpression of oncogenes (JUNB, SATB1, pSTAT3, SOCS3) in lymphomatoid papulosis; frequent apoptosis; complete spontaneous regression in lymphomatoid papulosis; and partial spontaneous regression in cutaneous ALCL. Unlike CD30 cutaneous lymphoproliferative disorder, BIA-ALCL cannot be readily observed over time to study the different steps in progression to ALCL. BIA-ALCL also shares features of lymphomas of mucosa-associated lymphoid tissue, which are clinically indolent, initially localized, antigen driven, and caused by Gram-negative bacteria. Further studies of cytokines, clonality, mutations, and other biomarkers are needed to identify possible premalignant steps in the evolution of benign late seromas to BIA-ALCL.


Double-Step Machine Learning Based Procedure for HFOs Detection and Classification.
The need for automatic detection and classification of high-frequency oscillations (HFOs) as biomarkers of the epileptogenic tissue is strongly felt in the clinical field. In this context, the employment of artificial intelligence methods could be the missing piece to achieve this goal. This work proposed a double-step procedure based on machine learning algorithms and tested it on an intracranial electroencephalogram (iEEG) dataset available online. The first step aimed to define the optimal length for signal segmentation, allowing for an optimal discrimination of segments with HFO relative to those without. In this case, binary classifiers have been tested on a set of energy features. The second step aimed to classify these segments into ripples, fast ripples and fast ripples occurring during ripples. Results suggest that LDA applied to 10 ms segmentation could provide the highest sensitivity (0.874) and 0.776 specificity for the discrimination of HFOs from no-HFO segments. Regarding the three-class classification, non-linear methods provided the highest values (around 90%) in terms of specificity and sensitivity, significantly different to the other three employed algorithms. Therefore, this machine-learning-based procedure could help clinicians to automatically reduce the quantity of irrelevant data.


Detecting activity locations from raw GPS data: a novel kernel-based algorithm.
Health studies and mHealth applications are increasingly resorting to tracking technologies such as Global Positioning Systems (GPS) to study the relation between mobility, exposures, and health. GPS tracking generates large sets of geographic data that need to be transformed to be useful for health research. This paper proposes a method to test the performance of activity place detection algorithms, and compares the performance of a novel kernel-based algorithm with a more traditional time-distance cluster detection method. A set of 750 artificial GPS tracks containing three stops each were generated, with various levels of noise.. A total of 9,000 tracks were processed to measure the algorithms' capacity to detect stop locations and estimate stop durations, with varying GPS noise and algorithm parameters. The proposed kernel-based algorithm outperformed the traditional algorithm on most criteria associated to activity place detection, and offered a stronger resilience to GPS noise, managing to detect up to 92.3% of actual stops, and estimating stop duration within 5% error margins at all tested noise levels. Capacity to detect activity locations is an important feature in a context of increasing use of GPS devices in health and place research. While further testing with real-life tracks is recommended, testing algorithms' performance with artificial track sets for which characteristics are controlled is useful. The proposed novel algorithm outperformed the traditional algorithm under these conditions.


Modeling Chemical Reactions in Alkali Carbonate-Hydroxide Electrolytes with Deep Learning Potentials.
We developed a deep potential machine learning model for simulations of chemical reactions in molten alkali carbonate-hydroxide electrolyte containing dissolved CO2, using an active learning procedure. We tested the deep neural network (DNN) potential and training procedure against reaction kinetics, chemical composition, and diffusion coefficients obtained from density functional theory (DFT) molecular dynamics calculations. The DNN potential was found to match DFT results for the structural, transport, and short-time chemical reactions in the melt. Using the DNN potential, we extended the time scales of observation to 2 ns in systems containing thousands of atoms, while preserving quantum chemical accuracy. This allowed us to reach chemical equilibrium with respect to several chemical species in the melt. The approach can be generalized for a broad spectrum of chemically reactive systems.


The effects of trypsin and phospholipase C on insulin binding and action in the isolated adipocyte.
The effect of alterations to the insulin receptor on the insulin sensitivity of isolated adipocytes was studied. Receptor changes were induced by treatment of adipocytes with either phospholipase C or trypsin. After enzyme treatment, binding of insulin to insulin receptors and insulin-mediated glucose metabolism were examined. Exposure of adipocytes to phospholipase C (2 units/ml) significantly increased insulin binding to the cells, but destroyed the ability of the cells to oxidize glucose. After treatment with trypsin (500 micrograms/ml) for 5 min, insulin binding to the adipocytes was significantly increased. This was shown to be due to an increase in insulin-receptor affinity. Metabolic studies showed that trypsin treatment led to an increase in basal glucose transport but markedly decreased the response to insulin at all concentrations tested. Adipocytes treated with trypsin showed no significant difference in basal glucose oxidation rates when compared with controls, but were less sensitive to insulin at low insulin concentrations, and showed a decreased maximum response at high insulin concentrations. In conclusion, these findings indicate a dissociation between induced changes in binding of insulin to insulin receptors and subsequent hormone action. The importance of post-receptor events in the biological action of insulin is highlighted.


Tamoxifen and gallstone formation in postmenopausal breast cancer patients: retrospective cohort study.
Tamoxifen is being used successfully in breast cancer patients as adjuvant hormonal therapy. The aim of this retrospective cohort study is to evaluate the impact of tamoxifen on gallstone formation in postmenopausal breast cancer patients. A total of 3165 patients who were treated for invasive breast cancer between 1990 and 1997 were reviewed. The data were collected from four university hospitals in a population-based registry. Among these patients, 2462 were excluded from the study owing to improper follow-up and other reasons. Premenopausal patients were also excluded. Of the 703 patients included in the study, 457 had received adjuvant therapy including tamoxifen, and the other 246 had not. Gallstone formation was assessed by annual abdominal ultrasonography. The mean follow-up period was 4.6 years (range 1-7 years). There were no significant differences between the groups of breast cancer patients treated with or without tamoxifen regarding the age of the patients at the time of breast cancer diagnosis, the age at menopause, the duration between the onset of menopause and the time the breast cancer was diagnosed, the presence of diabetes, and the body mass index. At the end of 5 years the incidence of gallstone formation in tamoxifen-treated patients was 37.4%, whereas it was 2.0% in patients who did not receive tamoxifen ( p < 0.0001). The incidences of gallstones being detected in 171 tamoxifen-treated patients were 0.4%, 3.7%, 24.4%, 33.1%, and 37.4% cumulatively during the first, second, third, fourth, and fifth years, respectively. Hence adjuvant tamoxifen therapy leads to gallstone formation in postmenopausal breast cancer patients and is most apparent after 3 years of treatment.


Randomised controlled trial assessing the acceptability of GyneFix versus Gyne-T380S for emergency contraception.
To assess insertion-linked pain and the short-term user-acceptability and safety of the GyneFix as compared with T-framed intrauterine devices (IUDs). A randomised controlled trial in an outpatient clinic setting. Women requesting an IUD for emergency contraception (EC) were allocated to either the short-term arm (GyneFix versus Nova-T200, or the long-term arm (GyneFix versus Gyne-T380S, and then randomised within each group. Visual analogue scores were used to assess the women's perception of the pain associated with insertion, which was patient-blinded. Follow-up was double-blinded, at 6 weeks, with bleeding and pain recorded over this time. A total of 175 women received an IUD in the long-term arm. The short-term arm was discontinued due to low recruitment (17 women at 20 months) and therefore the results relate to the long-term arm only. Outcome was known in 98% of subjects. The actual insertion procedure was scored as more painful for the GyneFix, both by the women (p = 0.013) and the doctors making their assessment of the women's pain (p = 0.04). The women with GyneFix described less pain in the subsequent 30 days after insertion (p = 0.005). Only 13% of women with GyneFix requested removal as compared with 20% with Gyne-T380S, with the difference being attributed to removal due to pain. The bleeding pattern was similar for those using GyneFix and Gyne-T380S. Our study suggests that although the actual fitting may be more painful, pain is less during the 6 weeks after insertion of GyneFix and fewer women discontinue its use because of pain, as compared with Gyne-T380S. The high overall continuation rate of all emergency IUDs at 6 weeks and low morbidity seen in this study favours more frequent IUD insertion where unprotected intercourse has occurred, given also its higher efficacy over oral hormonal EC.


Iterative Molecular Dynamics-Rosetta Membrane Protein Structure Refinement Guided by Cryo-EM Densities.
Knowing atomistic details of proteins is essential not only for the understanding of protein function but also for the development of drugs. Experimental methods such as X-ray crystallography, NMR, and cryo-electron microscopy (cryo-EM) are the preferred forms of protein structure determination and have achieved great success over the most recent decades. Computational methods may be an alternative when experimental techniques fail. However, computational methods are severely limited when it comes to predicting larger macromolecule structures with little sequence similarity to known structures. The incorporation of experimental restraints in computational methods is becoming increasingly important to more reliably predict protein structure. One such experimental input used in structure prediction and refinement is cryo-EM densities. Recent advances in cryo-EM have arguably revolutionized the field of structural biology. Our previously developed cryo-EM-guided Rosetta-MD protocol has shown great promise in the refinement of soluble protein structures. In this study, we extended cryo-EM density-guided iterative Rosetta-MD to membrane proteins. We also improved the methodology in general by picking models based on a combination of their score and fit-to-density during the Rosetta model selection. By doing so, we have been able to pick models superior to those with the previous selection based on Rosetta score only and we have been able to further improve our previously refined models of soluble proteins. The method was tested with five membrane spanning protein structures. By applying density-guided Rosetta-MD iteratively we were able to refine the predicted structures of these membrane proteins to atomic resolutions. We also showed that the resolution of the density maps determines the improvement and quality of the refined models. By incorporating high-resolution density maps (∼4 Å), we were able to more significantly improve the quality of the models than when medium-resolution maps (6.9 Å) were used. Beginning from an average starting structure root mean square deviation (RMSD) to native of 4.66 Å, our protocol was able to refine the structures to bring the average refined structure RMSD to 1.66 Å when 4 Å density maps were used. The protocol also successfully refined the HIV-1 CTD guided by an experimental 5 Å density map.


Hematoma after mastectomy with immediate reconstruction: an analysis of risk factors in 883 patients.
Mastectomy followed by breast reconstruction presents unique circumstances, such as 2 operating teams, that may affect the likelihood of postoperative bleeding. This study evaluates risk factors for hematoma formation in patients undergoing mastectomy with immediate implant reconstruction. The charts of 883 patients (1199 breasts) who underwent mastectomy and immediate tissue expander reconstruction between April 1998 and August 2008 at a single institution were retrospectively reviewed. Demographic and operative factors and information on hematoma location were recorded. Fisher exact test, Student t test, and multiple linear regression were used for statistical analysis. There were no differences in preoperative, operative, and oncologic characteristics between hematoma (n = 28 breasts) and nonhematoma (n = 1171 breasts) groups. Multiple linear regression analysis revealed no independent risk factors for hematoma formation, except an individual mastectomy and reconstructive surgeon (odds ratio, 3.58; 95% confidence interval, 1.03-12.37; P = 0.03; odds ratio, 2.54; 95% confidence interval, 1.06-6.08; P = 0.03, respectively). Most hematomas were diagnosed on postoperative day 0 or 1 (23/28, 82.1%) and found to originate from the pectoralis muscle (14/28, 50.0%) or axillary region (6/28, 21.4%). The risk of postoperative hematoma after mastectomy with immediate reconstruction is not affected by any measurable preoperative, operative, or oncologic factors. With no definitive risk factor for bleeding, surgeons should remain meticulous and vigilant throughout the operation. In particular, hemostasis should be focused on the chest wall musculature given its propensity for being the primary source of hematoma formation.


Epidemiology and distribution of Plasmodium vivax malaria in Sudan.
Plasmodium vivax malaria has been recognised as an important cause of morbidity in several African countries. The prevalence was previously estimated as 2-5% in eastern Sudan. These estimates are observed to be rising and spreading continuously. The present study was undertaken to investigate the situation of distribution and epidemiology of P. vivax malaria in Sudan. Cross-sectional malaria surveys carried out in hospitals and health centres covered 21 sites in 10 states. Data and blood samples were collected from 1226 clinically investigated suspected malaria cases of both genders and all ages. Microscopically detected malaria parasites were confirmed by PCR. The overall prevalence of P. vivax among the malaria cases was 26.6%. The prevalence showed significant variations between the states (p<0.001), which could be explained by differences in population movement, the presence of refugees and proximity to endemic neighbouring countries. It also varied significantly with residence status (p<0.001), reflecting the stability of transmission. Although malaria in Sudan is still largely attributed to Plasmodium falciparum, P. vivax has been rising with worrying proportions and spreading to new areas. The emergence and marked increase of P. vivax poses new challenges to malaria treatment and control in Sudan.


World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a serious public health problem, compromising the management and control of gonorrhoea globally. Resistance in N. gonorrhoeae to ceftriaxone, the last option for first-line empirical monotherapy of gonorrhoea, has been reported from many countries globally, and sporadic failures to cure especially pharyngeal gonorrhoea with ceftriaxone monotherapy and dual antimicrobial therapies (ceftriaxone plus azithromycin or doxycycline) have been confirmed in several countries. In 2018, the first gonococcal isolates with ceftriaxone resistance plus high-level azithromycin resistance were identified in England and Australia. The World Health Organization (WHO) Global Gonococcal Antimicrobial Surveillance Program (GASP) is essential to monitor AMR trends, identify emerging AMR and provide evidence for refinements of treatment guidelines and public health policy globally. Herein we describe the WHO GASP data from 67 countries in 2015-16, confirmed gonorrhoea treatment failures with ceftriaxone with or without azithromycin or doxycycline, and international collaborative actions and research efforts essential for the effective management and control of gonorrhoea. In most countries, resistance to ciprofloxacin is exceedingly high, azithromycin resistance is present and decreased susceptibility or resistance to ceftriaxone has emerged. Enhanced global collaborative actions are crucial for the control of gonorrhoea, including improved prevention, early diagnosis, treatment of index patient and partner (including test-of-cure), improved and expanded AMR surveillance (including surveillance of antimicrobial use and treatment failures), increased knowledge of correct antimicrobial use and the pharmacokinetics and pharmacodynamics of antimicrobials and effective drug regulations and prescription policies (including antimicrobial stewardship). Ultimately, rapid, accurate and affordable point-of-care diagnostic tests (ideally also predicting AMR and/or susceptibility), new therapeutic antimicrobials and, the only sustainable solution, gonococcal vaccine(s) are imperative.


Does outcome of neuropsychological treatment in patients with unilateral spatial neglect after stroke affect functional outcome?
Unilateral spatial neglect (USN) after stroke is associated to severe disability and to a poor rehabilitation outcome. However it is still unclear if a reduction of USN after a specific neurophsycological treatment could also favor the functional recovery. The first aim of this study was to determine if low responders to neuropsychological treatment of unilateral spatial neglect may have a worse functional prognosis for activities of daily living. The second aim was to investigate which variables can predict a low response to neuropsychological treatment. Observational study. Neurorehabilitation hospital in Italy. Two hundred inpatients with the diagnosis of ischemic stroke were screened in this observational study. Inclusion criteria were: patients in subacute phase of first ischemic stroke in right hemisphere. Exclusion criteria were: presence of previous and/or other disabling pathologies, medical conditions contraindicating physical therapy. Data of 73 patients who performed neurorehabilitation and visual scanning training for reducing USN were analysed, while the remaining others were excluded for at least one of the following reasons: hemorrhagic lesions, presence of other chronic disabling pathologies, contraindications for therapy. USN was evaluated using: Letter Cancellation Test, Barrage Test, Sentence Reading Test and Wundt-Jastrow Area Illusion Test. Barthel Index (BI), Beck Depression Inventory, and Canadian Neurological Scale were also administered. According to the aim of the study, forward binary logistic regressions were performed to evaluate the effects of different factors on functional recovery. Three factors were identified as predictors of low effectiveness in terms of BI-score: older age (odds ratio OR=9.882, P=0.002), severity of disease at admission (OR=12.594, P=0.002) and being low responders to neuropsychological treatment (OR=3.847, P=0.027). Further, the initial barrage score (OR=3.313, P=0.027) and the initial BI-score (OR=3.252, P=0.039) effectively predict the response to neuropsychological treatment. The outcome of the whole rehabilitation resulted affected by the outcome of neuropsychological treatment in patients with USN, being a low score at Barrage test at the beginning of therapy a negative predictor of USN recovery. Patients with USN after stroke can benefit of a specific training for reducing USN also in terms of functional outcome. Further, the simple use of Barrage test could provide important prognostic information about recovery.


[Immunobiological features of bacterial cells of medical biofilms].
Biofilm is a integrated multucellular organism with own cycle of development, cooperative behavior of units forming it, which coordinated by QS-system based on production of signal molecules or autoinductors and ability of bacteria to receive these signals. Presence ofbacteria attached to surface of biomedical devices and formation of bacterial biofilms in the microorganism could lead to chronic inflammation, which characterized by presence of macrophages and lymphocytes in the focus of inflammation as well as proliferation of connective tissue, accumulation of matrix proteins and stimulation ofangiogenesis. Process of biofilm formation associated with activation of QS-system of different agents including potentially dangerous bacteria plays certain role in exacerbation of gastric and duodenal ulcer diseases, Crohn's disease, myocarditis, asthma, diabetes mellitus, cardiovascular and other somatic diseases. Detachment of biofilm could lead to enter ofbac-teria in bloodsream and vascular embolism. Issues related to ability of bacteria of biofilms to modulate immune response and potential for the emerging response to influence the biofilm growth and level of expression of bacterial virulence are discussed. Modem views on mechanisms of interaction of bacteria of exopolysaccharide biofilm with host's immune response factors are reviewed. The most perspective ways to control for biofilm formation and their disruption using newly developing drugs are outlined.


The torsion of the proximal femur in cementless total hip arthroplasty: a 3-dimensional evaluation.
The anatomy of the proximal femur at the time of total hip arthroplasty has been widely studied but the horizontal plane was never considered, or only limited to the torsion of the femoral neck. Using CT-scan images from a group of 178 patients scheduled for cementless total hip arthroplasty (THA), we analysed the evolution of the torsion of the proximal femoral metaphysis, in reference to the posterior bicondylar plane of the femur. The evolution of the torsion, between 20 mm below the centre of the lesser trochanter and 20 mm above, was evaluated. In cases of primary osteoarthritis, osteonecrosis, rheumatoid arthritis and epiphysiolysis capitis femoris, the mean torsion decreased from 46° to 20° without significant differences in average values between the different diagnoses, but important individual variations were found. In the groups of dysplasia and congenital hip dislocation, the torsion values were significantly higher, decreasing in mean from 59° to 25° and 63° to 34° respectively, and with important individual variations. These data are important when using cementless femoral stems, since an ideal fit-and-fill in the proximal femur zone has been shown to positively influence bone ingrowth of the stem. However, a strict adaptation of the stem to the medullary canal, without considering its torsion, can lead to an increased or decreased torsion of the prosthesis neck and thus to an instability of the arthroplasty. For these reasons, if a perfect adaptation of the stem to the intramedullary anatomy and an optimal reconstruction of the extramedullary anatomy are to be achieved, 3-dimensional planning should ideally be obtained for every patient. This will allow the best stem choice adapted to every single patient and every kind of anatomy.


Convergence of normal stem cell and cancer stem cell developmental stage: Implication for differential therapies.
Increased evidence shows that normal stem cells may contribute to cancer development and progression by acting as cancer-initiating cells through their interactions with abnormal environmental elements. We postulate that normal stem cells and cancer stem cells (CSC) possess similar mechanisms of self-renewal and differentiation. CSC can be the key to the elaboration of anti-cancer-based therapy. In this article, we focus on a controversial new theme relating to CSC. Tumorigenesis may have a critical stage characterized as a "therapeutic window", which can be identified by association of molecular, biochemical and biological events. Identifying such a stage can allow the production of more effective therapies (e.g. manipulated stem cells) to treat several cancers. More importantly, confirming the existence of a similar therapeutic window during the conversion of normal stem cells to malignant CSC may lead to targeted therapy specifically against CSC. This conversion information may be derived from investigating the biological behaviour of both normal stem cells and cancerous stem cells. Currently, there is little knowledge about the cellular and molecular mechanisms that govern the initiation and maintenance of CSC. Studies on co-evolution and interdependence of cancer with normal tissues may lead to a useful treatment paradigm of cancer. The crosstalk between normal stem cells and cancer formation may converge developmental stages of different types of stem cells (e.g. normal stem cells, CSC and embryonic stem cells). The differential studies of the convergence may result in novel therapies for treating cancers.


Do nanoparticles have a future in dermal drug delivery?
More and more investigations confirm that nanoparticles are incapable of overcoming the intact skin barrier in vivo. Do nanoparticles still have a future in dermal drug delivery? Unlike many other topically applied substances, nanoparticles have not been reported to utilize the intercellular penetration pathway and preferentially make use of the follicular penetration pathway. Deep penetration into the follicular ducts has been described for a variety of particles and appears to be strongly influenced by particle size. For targeted drug delivery, smart nanoparticles are required which are able to release their loaded drugs subsequent to internal or external trigger stimuli, and thereby enable the translocation of the active agents into the viable epidermis. In the recent manuscript, three nanoparticles systems are summarized and compared which release their model drugs upon different trigger mechanisms. The BSA hydrogel nanoparticles release their model drug TRITC-dextran by passive diffusion due to a concentration gradient via a porous surface. The protease-triggered controlled release BSA nanoparticles release their model drug if they are applied simultaneously with protease nanoparticles, resulting in an enzymatic degradation of the particles and a release of the model drug FITC. Finally, the IR-triggered controlled release AuNP-doped BSA nanoparticles release their model drug FITC after photoactivation with wIRA. For all three nanoparticle systems, the release of their model drugs could be observed. For the first nanoparticle system, only low follicular penetration depths were found which might by due do an agglomeration effect. For the last two nanoparticle systems, deep follicular penetration and even an uptake by the sebaceous glands were verified. In conclusion, it could be demonstrated that nanoparticles do have a future in dermal drug delivery if smart nanoparticle systems are utilized which are able to release their drug at specific times and locations within the hair follicle.


Temperature-dependent isotope effects in soybean lipoxygenase-1: correlating hydrogen tunneling with protein dynamics.
The hydrogen-atom transfer in soybean lipoxygenase-1 (SLO) exhibits a large kinetic isotope effect on k(cat) (KIE = 81) near room temperature and a very weak temperature dependence (E(act) = 2.1 kcal/mol). These properties are consistent with H small middle dot transfer that occurs entirely by a tunneling event. Mutants of SLO were prepared, and the temperature dependence of the KIE was measured, to test for alterations in the tunneling behavior. All mutants studied exhibit KIEs of similar, large magnitude at 30 degrees C, despite an up to 3 orders of magnitude change in k(cat). E(act) for two of the mutants (Leu(754) --> Ala, Leu(546) --> Ala) is larger than for wild-type (WT), and the KIE becomes slightly more temperature dependent. In contrast, Ile(553) --> Ala exhibits k(cat) and E(act) parameters similar to wild-type soybean lipoxygenase-1 (WT-SLO) for protiated substrate; however, the KIE is markedly temperature dependent. The behavior of the former two mutants could reflect increased reorganization energies (lambda), but the behavior of the latter mutant is inconsistent with this description. We have invoked a full H* tunneling model (Kuznetsov, A. M.; Ulstrup, J. Can. J. Chem. 1999, 77, 1085-1096) to explain the temperature dependence of the KIE, which is indicative of the extent to which distance sampling (gating) modulates hydrogen transfer. WT-SLO exhibits a very small E(act) and a nearly temperature-independent KIE, which was modeled as arising from a compressed hydrogen transfer distance with little modulation of the hydrogen transfer distance. The observations on the Leu(754) --> Ala and Leu(546) --> Ala mutants were modeled as arising from a slightly less compressed active site with greater modulation of the hydrogen transfer distance by environmental dynamics. Finally, the observed behavior of the Ile(553) --> Ala mutant indicates a relaxed active site with extensive involvement of gating to facilitate hydrogen transfer. We conclude that WT-SLO has an active site structure that is well organized to support hydrogen tunneling and that mutations perturb structural elements that support hydrogen tunneling. Modest alterations in active site residues increase lambda and/or increase the hydrogen transfer distance, thereby affecting the probability that tunneling can occur. These studies allow the detection and characterization of a protein-gating mode in catalysis.


Imaging Findings in Patients with Zoster-Associated Plexopathy.
Herpes zoster is a reactivation of the latent varicella zoster virus. Among the complications of herpes zoster is zoster-associated limb paresis. The clinical and imaging features of patients with zoster-associated limb paresis due to plexopathies (zoster-associated plexopathy) have had limited description in the literature. The Mayo Clinic patient data base was searched by diagnostic code for patients diagnosed with herpes zoster between January 1, 1996, and September 30, 2012. Patients who met the inclusion criteria for zoster-associated limb paresis or herpes zoster with MRIs obtained were reviewed. Ten patients with zoster-associated plexopathy were identified. Imaging abnormalities were found in 70% of patients. Secondary denervation changes in shoulder girdle muscles and nerve T2 signal hyperintensity were the most frequent abnormalities (50%), followed by nerve enlargement (20%). Enhancement was not evident in any cases despite early imaging in 80% of the cohort. These results demonstrate the clinical utility of MR imaging in confirming the diagnosis of zoster-associated plexopathy.


Endocrine Therapy in Premenopausal Hormone Receptor Positive/Human Epidermal Growth Receptor 2 Negative Metastatic Breast Cancer: Between Guidelines and Literature.
There is growing interest in the endocrine treatment (ET) of premenopausal women with hormone receptor positive (HR+) metastatic breast cancer (MBC). This review summarizes available data on endocrine therapy for this patient subset and aims to define the most appropriate treatment approach. The combination of luteinizing hormone-releasing hormone (LHRH) agonists plus tamoxifen seems effective and safe and is considered as being superior to either approach alone; still, single-agent therapy remains an acceptable treatment option. Due to their mechanism of action, aromatase inhibitors alone are not suitable for the treatment of premenopausal patients, but the combination with LHRH agonists may result in excellent disease control. Fulvestrant, in conjunction with LHRH agonists, also yields interesting results regarding clinical benefit rate and time to progression; currently, other orally available selective estrogen receptor downregulators are under clinical evaluation. Recently, targeted drugs have been added to ET in order to reverse endocrine resistance, but only limited information regarding their activity in premenopausal patients is available. The cyclin dependent kinase 4 and 6 inhibitor palbociclib when combined with fulvestrant and LHRH agonists was shown to prolong progression-free survival over endocrine therapy alone in pretreated patients; similar results were obtained with the addition of abemacicilib or ribociclib to endocrine therapy. Currently, activity of the mammalian target of rapamycin inhibitor everolimus in combination with letrozole and goserelin is under assessment in premenopausal patients after progression on tamoxifen (MIRACLE trial). This review provides clinicians with an overview on the available data regarding endocrine treatment of hormone receptor positive (HR+) metastatic breast cancer (MBC) in premenopausal women and summarizes the treatment options available in routine clinical practice. Knowledge of an up-to-date therapeutic approach in women with premenopausal HR+ MBC will lead to better disease management, thereby improving disease control and quality of life while minimizing side effects.


Multispectral optoacoustic and MRI coregistration for molecular imaging of orthotopic model of human glioblastoma.
Multi-modality imaging methods are of great importance in oncologic studies for acquiring complementary information, enhancing the efficacy in tumor detection and characterization. We hereby demonstrate a hybrid non-invasive in vivo imaging approach of utilizing magnetic resonance imaging (MRI) and Multispectral Optoacoustic Tomography (MSOT) for molecular imaging of glucose uptake in an orthotopic glioblastoma in mouse. The molecular and functional information from MSOT can be overlaid on MRI anatomy via image coregistration to provide insights into probe uptake in the brain, which is verified by ex vivo fluorescence imaging and histological validation. In vivo MSOT and MRI imaging of an orthotopic glioma mouse model injected with IRDye800-2DG. Image coregistration between MSOT and MRI enables multifaceted (anatomical, functional, molecular) information from MSOT to be overlaid on MRI anatomy images to derive tumor physiological parameters such as perfusion, haemoglobin and oxygenation.


Oneiroid syndrome: a concept of use for western psychiatry.
Oneiroid syndrome (OS), or dream-like fantastic delusional derangement of consciousness, is characterized by a kaleidoscopic quality of psychopathological experiences, wherein reality, illusions and hallucinations are merged into one. It is typically accompanied by motor and, in particular, catatonic disturbances. This syndrome is an uncommon psychiatric state, which is hardly mentioned in standard psychiatric textbooks. OS is a neglected entity among DSM-oriented psychiatrists because it deals with a phenomenological approach in contrast to the European attitude, which deals with detailed clinical descriptions. Here, we propose detailed clinical descriptions with a number of consecutive stages of the OS development, illustrated by two vignettes with typical variants of oneiroid syndrome, in order to raise the awareness of psychiatrists who are not familiar with this state, and to try to open a window to the inner life of those patients suffering from this syndrome. These cases may also serve as illustration of certain principles which, when understood, may be found to lead in turn to a deeper knowledge of the psychopathology of other more commonplace conditions.


Delivering therapeutic cannabinoids via skin: Current state and future perspectives.
Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date.


Artificial intelligence: Machine learning approach for screening large database and drug discovery.
Recent research in drug discovery dealing with many faces difficulties, including development of new drugs during disease outbreak and drug resistance due to rapidly accumulating mutations. Virtual screening is the most widely used method in computer aided drug discovery. It has a prominent ability in screening drug targets from large molecular databases. Recently, a number of web servers have developed for quickly screening publicly accessible chemical databases. In a nutshell, deep learning algorithms and artificial neural networks have modernised the field. Several drug discovery processes have used machine learning and deep learning algorithms, including peptide synthesis, structure-based virtual screening, ligand-based virtual screening, toxicity prediction, drug monitoring and release, pharmacophore modelling, quantitative structure-activity relationship, drug repositioning, polypharmacology, and physiochemical activity. Although there are presently a wide variety of data-driven AI/ML tools available, the majority of these tools have, up to this point, been developed in the context of non-communicable diseases like cancer, and a number of obstacles have prevented the translation of these tools to the discovery of treatments against infectious diseases. In this review various aspects of AI and ML in virtual screening of large databases were discussed. Here, with an emphasis on antivirals as well as other disease, offers a perspective on the advantages, drawbacks, and hazards of AI/ML techniques in the search for innovative treatments.


Biogenesis of thylakoid membranes is controlled by light intensity in the conditional chlorophyll b-deficient CD3 mutant of wheat.
Biogenesis of thylakoid membranes in the conditional chlorophyll b-deficient CD3 mutant of wheat is dramatically altered by relatively small differences in the light intensity under which seedlings are grown. When the CD3 mutant is grown at 400 microE/m2 S (high light, about one-fifth full sunlight) plants are deficient in chlorophyll b (chlorophyll a/b ratio greater than 6.0) and lack or contain greatly reduced amounts of the chlorophyll a/b-binding complexes CPII/CPII (mobile or peripheral LHCII), CP29, CP24 and LHCI, as shown by mildly denaturing 'green gel' electrophoresis, by fully denaturing SDS-PAGE, and by Western blot analysis. High light CD3 chloroplasts display an unusual morphology characterized by large, sheet-like stromal thylakoids formed into parallel unstacked arrays and a limited number of small grana stacks displaced toward the edges of the arrays. Changes in the supramolecular organization of CD3 thylakoids, seen with freeze-fracture electron microscopy, include a reduction in the size of EFs particles, which correspond to photosystem II centers with variable amounts of attached LHCII, and a redistribution of EF particles from the stacked to the unstacked regions. When CD3 seedlings are grown at 150 microE/m2 S (low light) there is a substantial reversal of all of these effects. Thus, chlorophyll b and the chlorophyll a/b-binding proteins accumulate to near wild-type levels (chlorophyll a/b ratio = 3.5-4.5) and thylakoid morphology is more nearly wild type in appearance. Growth of the CD3 mutant in the presence of chloramphenicol stimulates the accumulation of chlorophyll b and its binding proteins (Duysen, M. E., T. P. Freeman, N. D. Williams, and L. L. Huckle. 1985. Plant Physiol. 78:531-536). We show that this partial rescue of the CD3 high light phenotype is accompanied by large changes in thylakoid structure. The CD3 mutant, which defines a new class of chlorophyll b-deficient phenotype, is discussed in the more general context of chlorophyll b deficiency.


Facile Fabrication of "Tacky", Stretchable, and Aligned Carbon Nanotube Sheet-Based Electronics for On-Skin Health Monitoring.
Point-of-care monitoring of physiological signals such as electrocardiogram, electromyogram, and electroencephalogram is essential for prompt disease diagnosis and quick treatment, which can be realized through advanced skin-worn electronics. However, it is still challenging to design an intimate and nonrestrictive skin-contact device for physiological measurements with high fidelity and artifact tolerance. This research presents a facile method using a "tacky" surface to produce a tight interface between the ACNT skin-like electronic and the skin. The method provides the skin-worn electronic with a stretchability of up to 70% strain, greater than that of most common epidermal electrodes. Low-density ACNT bundles facilitate the infiltration of adhesive and improve the conformal contact between the ACNT sheet and the skin, while dense ACNT bundles lessen this effect. The stretchability and conformal contact allow the ACNT sheet-based electronics to create a tight interface with the skin, which enables the high-fidelity measurement of physiological signals (the Pearson's coefficient of 0.98) and tolerance for motion artifacts. In addition, our method allows the use of degradable substrates to enable reusability and degradability of the electronics based on ACNT sheets, integrating "green" properties into on-skin electronics.


Structure-Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model.
Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure-activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.


Childhood adversity and psychiatric disorder in young adulthood: An analysis of 107,704 Swedes.
Childhood adversity (CA) is associated with increased risks of psychiatric disorder in young adulthood, but details in this association are less known. We aimed to explore the association of a range of CA indicators with psychiatric disorder in young adulthood, and the impact of age at exposure, disorder type and accumulation of indicators. We capitalized on Sweden's extensive and high-quality registers and analyzed a cohort of all Swedes (N = 107,704) born in Stockholm County 1987-1991. Adversities included familial death, parental substance misuse and psychiatric disorder, parental criminality, parental separation, public assistance recipiency and residential instability. Age at exposure was categorized as: 0-6.9 years (infancy and early childhood), 7-11.9 years (middle childhood), and 12-14 years (early adolescence). Psychiatric disorders after age 15 were defined from ICD codes through registers. Risks were calculated as Hazard Ratios (HR) with 95% confidence intervals (CI). Results showed that exposure to at least one CA was associated with an increased risk of psychiatric disorder (HR 1.4, 95% CI: 1.3-1.4). Risks were increased for mood, anxiety, and psychotic disorders and ADHD but not for eating disorders. The risk varied with type of disorder but was similar for all exposure periods. Individuals with multiple (3+) CAs had a two-fold risk of psychiatric disorder (HR 2.0, 95% CI: 1.9-2.1). In conclusion, our findings support the long-term negative impact of CA on mental health, regardless of developmental period of exposure. Given that experience of CA is common, efforts should be put to alleviate the burden of childhood adversities for children, particularly among the most disadvantaged.