A genotyping array for the globally invasive vector mosquito, Aedes albopictus.

BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health. METHODS: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions. RESULTS: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture. CONCLUSIONS: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS.

Predicting the risks and recognizing the signs: a two-year prospective population-based study on pregnant women with uterine rupture in The Netherlands.

OBJECTIVE: To estimate the incidence of uterine rupture in the Netherlands and evaluate risk indicators prelabour and during labor of women with adverse maternal and/or perinatal outcome. METHODS: This is a population-based nationwide study using the Netherlands Obstetrics Surveillance System (NethOSS). We performed a two-year registration of pregnant women with uterine rupture. The first year of registration included both women with complete uterine rupture and women with incomplete (peritoneum intact) uterine rupture. The second year of registration included women with uterine rupture with adverse maternal and/or perinatal outcome. We collected maternal and obstetric characteristics, clinical signs, and symptoms during labor and CTG abnormalities. The main outcome measures were incidence of complete uterine rupture and uterine rupture with adverse outcome and adverse outcome defined as major obstetric hemorrhage, hysterectomy, embolization, perinatal asphyxia and/or (neonatal) intensive care unit admission. RESULTS: We registered 41 women with a complete uterine rupture (incidence: 2.5 per 10,000 births) and 35 women with uterine rupture with adverse outcome (incidence: 0.9 per 10,000 births). No adverse outcomes were found among women with incomplete uterine rupture. Risk indicators for adverse outcome included previous cesarean section, higher maternal age, gestational age <37 weeks, augmentation of labor, migration background from Sub-Saharan Africa or Asia. Compared to women with uterine rupture without adverse outcomes, women with adverse outcome more often expressed warning symptoms during labor such as abdominal pain (OR 3.34, 95%CI 1.26-8.90) and CTG abnormalities (OR 9.94, 95%CI 2.17-45.65). These symptoms were present most often 20 to 60 min prior to birth. CONCLUSION: Uterine rupture is a rare condition for which several risk indicators were identified. Maternal symptoms and CTG abnormalities are associated with adverse outcomes and time dependent. Further analysis could provide guidance to expedite delivery.

Tuberculin skin testing and QuantiFERON™-TB Gold Plus positivity among household contacts in Vietnam.

SETTING: TB infection (TBI) is diagnosed using the technique-dependent tuberculin skin test (TST) or costly, more accurate interferon-gamma release assays. The TST (⩾10 mm) threshold was indicated by previous research among household contacts in Vietnam, but routine implementation with a different tuberculin reagent showed unexpectedly low TST positivity. OBJECTIVE: TST (⩾5 mm and ⩾10 mm) results were compared to QuantiFERON™-TB Gold Plus (QFT) results in household contacts during community campaigns in 2020 and 2021. DESIGN: This was a cross-sectional multi-center implementation study. RESULTS: Among 1,330 household contacts in 2020, we found a TBI prevalence of 38.6% (QFT), similar to TST ⩾5 mm (37.4%) and higher than TST ⩾10 mm (13.1%). QFT+/TST+ was higher for TST ⩾5 mm (20.7%) than TST ⩾10 mm (9.4%). QFT was not discordant with TST ⩾5 mm (McNemar's test = 0.6, P = 0.5) but was discordant with TST ⩾10 mm (McNemar's test = 263.9, P < 0.01). Older age and Southern region increased odds for positive TST ⩾5 mm and QFT with weaker associations for TST ⩾10 mm. Agreement and discordance were similar in 2021 for 1,158 household contacts. CONCLUSION: Tuberculin reagents affect TST positivity rates. High TB burden countries should monitor reliability of TBI diagnosis, including tuberculin potency, cold chain, and TST technique to optimize eligibility for TB preventive treatment.

CONTEXTE: L'infection tuberculeuse (TBI) est diagnostiquée à l'aide du test cutané à la tuberculine (TST), qui dépend de la technique, ou de tests de libération de l'interféron-gamma, coûteux et plus précis. Des recherches antérieures ont indiqué que le TST (⩾10 mm) est généralement utilisé pour diagnostiquer la TB parmi les contacts familiaux au Vietnam ; la mise en œuvre de routine avec un réactif de tuberculine différent a montré une faible positivité inattendue du TST. OBJECTIF: Les résultats du TST (⩾5 mm et ⩾10 mm) ont été comparés aux résultats de QuantiFERON™-TB Gold Plus (QFT) chez les contacts familiaux au cours des campagnes communautaires de 2020 et 2021. MÉTHODE: Il s'agissait d'une étude transversale multicentrique de mise en œuvre. RÉSULTATS: Parmi 1 330 contacts familiaux en 2020, nous avons trouvé une prévalence de TBI de 38,6% (QFT), similaire au TST ⩾5 mm (37,4%) et plus élevée que le TST ⩾10 mm (13,1%). Le QFT+/TST+ était plus élevé pour le TST ⩾5 mm (20,7%) que pour le TST ⩾10 mm (9,4%). Le QFT n'était pas discordant avec le TST ≥5 mm (test de McNemar = 0,6 ; P = 0,5) mais était discordant avec le TST ⩾10 mm (test de McNemar = 263,9 ; P < 0,01). L'âge avancé et la région méridionale augmentaient les probabilités d'un TST positif ⩾5 mm et d'un QFT, avec des associations plus faibles pour un TST ⩾10 mm. La concordance et la discordance étaient similaires en 2021 pour 1 158 contacts familiaux. CONCLUSION: Les réactifs de tuberculine affectent les taux de positivité des TST. Les pays à forte charge de TB doivent surveiller la fiabilité du diagnostic de TBI, y compris la puissance de la tuberculine, la chaîne du froid et la technique du TST afin d'optimiser l'éligibilité au traitement préventif de la TB.

Soft tissue regeneration in animal models using grafts from adipose mesenchymal stem cells and peripheral blood fibrin gel.

OBJECTIVE: Our study aimed to evaluate the effect of soft tissue regeneration in nude mice using grafts made from the combination of adipocytes from fat tissue mesenchymal stem cells and fibrin gel from peripheral blood. MATERIALS AND METHODS: Mesenchymal stem cells were isolated from adipose tissue and identified according to ISCT criteria. The scaffold used was fibrin obtained from peripheral blood. The grafts in this study were generated by transferring mesenchymal stem cells onto a fibrin scaffold. Two types of grafts, the research sample (fibrin scaffold containing adipocytes differentiated from mesenchymal stem cells) and the control sample (fibrin scaffold only), were grafted under the dorsal skin of the same mouse. After each research period, samples were collected and evaluated by histological methods to observe the existence and growth of cells inside the grafts. RESULTS: The results showed that the study group's graft integrated better within the tissue when compared with the control group. In addition, the grafts in the study group showed the presence of cells with characteristic morphology of adipocytes one week after transplantation. In contrast, control samples showed dimorphous shapes and features mainly composed of non-homogenous fragments. CONCLUSIONS: These initial conclusions might be considered a first step in generating safe bio-compatible engineered grafts specifically usable in post-traumatic tissue regeneration procedures.

Evaporative water loss from dairy cows in climate-controlled respiration chambers.

The effects of ambient temperature (AT) on total evaporative water loss from dairy cows at different relative humidity (RH) and air velocity (AV) levels were studied. Twenty Holstein dairy cows with an average parity of 2.0 ± 0.7 and body weight of 687 ± 46 kg participated in the study. Two climate-controlled respiration chambers were used. The experimental indoor climate was programmed to follow a diurnal pattern with AT at night being 9°C lower than during the day. Night AT was gradually increased from 7 to 21°C and day AT was increased from 16°C to 30°C within an 8-d period, both with an incremental change of 2°C/d. The effect of 3 RH levels with a diurnal pattern were studied as well, with low values during the day and high values during the night: low (day, 30%; night, 50%), medium (day, 45%; night, 70%), and high (day, 60%; night, 90%). The effects of AV were studied during the daytime at 3 levels: no fan (0.1 m/s), fan at medium speed (1.0 m/s), and fan at high speed (1.5 m/s). The medium and high AV levels were only combined with medium RH. In total, there were 5 treatments with 4 replicates each. The animals had free access to feed and water. Based on the water balance principle inside the respiration chambers, the total evaporative water loss from dairy cows at a daily level was quantified by measuring the mass of water in the incoming and outgoing air, condensed water, added water from a humidifier, and evaporative water from a wet floor, drinking bowl, manure reservoir, and water bucket. Water evaporation from a sample skin area was measured with a ventilated skin box, and water evaporation, through respiration with a face mask. The results show that RH/AV levels had no significant effect on total evaporative water loss, whereas the interaction effect between RH/AV with AT was significant. Cows at a high RH had a tendency for a lower increasing rate of evaporative water loss compared with cows at a low RH (0.61 vs. 0.79 kg/d per 1°C increase of AT). Cows at medium and high AV levels had a greater increasing rate than cows at low AV (0.91 and 0.95 vs. 0.71 kg/d per 1°C increase of AT, respectively). The increase of evaporative heat loss from dairy cows was mainly a result of the increase in evaporation (of sweat) from the skin. The skin water evaporation determined with the water balance method (less evaporation from respiration) and the ventilated skin box method showed no significant difference. The implication of this study is that cows at a high AT depend mainly on evaporative cooling from the skin. The ventilated skin box method, measuring only a small part of the skin during a short period during the day, can be a convenient and accurate way to determine the total cutaneous evaporative water loss from cows.

COVID-19 vaccination: public preference and intention in Vietnam.

Backgrounds: Understanding public opinion in relation to vaccination is critical, as there are several COVID-19 vaccines approved for use in Vietnam. This study aimed to assess public COVID-19 vaccine preferences and intention in Can Tho, Vietnam. Methods: An analytical cross-sectional study was performed between September 20 and October 20, 2021. in people aged 18 and over living in Can Tho, Vietnam, A questionnaire captured demographic information, vaccination intention, preference for vaccine selection, and barriers and motivations related to COVID-19 vaccination. Predictors for vaccination willingness among unvaccinated people were determined using multivariable logistic regression. Results: Out of the proposed vaccines that have been approved by the Vietnam Ministry of Health, AstraZeneca (31.4%), Pfizer (23.5%), and Moderna (14.7%) were the most preferred by participants. Out of 1,470 respondents, 35.8% have received at least one vaccine dose, and of these, 76.9% intended to continue to receive vaccinations. Among the unvaccinated, 74.8% reported that they would be willing to complete the vaccination. Most participants stated that they would receive a COVID-19 vaccine if provided with adequate information on effectiveness and safety (92.7%). The possibility of side effects after vaccination (75.4%) was the most important barrier to vaccination. Education, health status, and prior flu-vaccination were associated with the intention to receive a COVID-19 vaccination among those who had not previously received one. Conclusions: Many unvaccinated adults were willing to receive a COVID-19 vaccination, with AstraZeneca being the preferred choice. These findings could help in the planning of vaccination campaigns to increase vaccination uptake in Vietnam.

Associations between patient-reported late effects and systemic cytokines in long-term survivors of head and neck cancer treated with radiotherapy.

PURPOSE: Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related quality of life of survivors. Knowledge on long-term late effects after radiotherapy (RT) and potential underlying biological mechanisms is lacking. We assessed the prevalence of xerostomia, dysphagia, and chronic fatigue (CF) in HNC survivors ≥ 5 years post-RT, and examined associations between pro-inflammatory cytokines and late effects. METHODS: In a cross-sectional study, 263 HNC survivors treated between 2007 and 2013 were enrolled. They completed validated questionnaires assessing xerostomia and dysphagia (the EORTC QLQ-H&N35), and CF (the Fatigue Questionnaire), and underwent blood sampling and clinical examination. Pro-inflammatory cytokines were analyzed in 262 survivors and 100 healthy age- and gender-matched controls. RESULTS: Median time since treatment was 8.5 years. The proportions of survivors reporting xerostomia, dysphagia, and CF were 58%, 31%, and 33%, respectively, with a preponderance of females. We found no significant associations between IL-6, IL-8, IP-10, TARC, TNF, or ENA-78 and the three late effects. The odds of having elevated levels of IL-6 and IP-10 were significantly higher in the survivors compared to the controls. CONCLUSIONS: More than one-third of long-term HNC survivors experienced xerostomia, dysphagia, and CF. Persistent inflammation, with elevated systemic cytokines, was not associated with these late effects, although HNC survivors had higher levels of some cytokines than the controls. IMPLICATIONS FOR CANCER SURVIVORS: This study provides new knowledge on late effects that can serve as grounds for informing patients with HNC about risk of late effects more than 5 years after RT.

Effects of increasing air temperature on skin and respiration heat loss from dairy cows at different relative humidity and air velocity levels.

The focus of this study was to identify the effects of increasing ambient temperature (T) at different relative humidity (RH) and air velocity (AV) levels on heat loss from the skin surface and through respiration of dairy cows. Twenty Holstein dairy cows with an average parity of 2.0 ± 0.7 and body weight of 687 ± 46 kg participated in the study. Two climate-controlled respiration chambers were used. The experimental indoor climate was programmed to follow a diurnal pattern with ambient T at night being 9°C lower than during the day. Night ambient T was gradually increased from 7 to 21°C and day ambient T was increased from 16 to 30°C within an 8-d period, both with an incremental change of 2°C per day. A diurnal pattern for RH was created as well, with low values during the day and high values during the night (low: RH_l = 30-50%; medium: RH_m = 45-70%; and high: RH_h = 60-90%). The effects of AV were studied during daytime at 3 levels (no fan: AV_l = 0.1 m/s; fan at medium speed: AV_m = 1.0 m/s; and fan at high speed: AV_h = 1.5 m/s). The AV_m and AV_h were combined only with RH_m. In total, there were 5 treatments with 4 replicates (cows) for each. Effects of short and long exposure time to warm condition were evaluated by collecting data 2 times a day, in the morning (short: 1-h exposure time) and afternoon (long: 8-h exposure time). The cows were allowed to adapt to the experimental conditions during 3 d before the main 8-d experimental period. The cows had free access to feed and water. Sensible heat loss (SHL) and latent heat loss (LHL) from the skin surface were measured using a ventilated skin box placed on the belly of the cow. These heat losses from respiration were measured with a face mask covering the cow's nose and mouth. The results showed that skin SHL decreased with increasing ambient T and the decreasing rate was not affected by RH or AV. The average skin SHL, however, was higher under medium and high AV levels, whereas it was similar under different RH levels. The skin LHL increased with increasing ambient T. There was no effect of RH on the increasing rate of LHL with ambient T. A larger increasing rate of skin LHL with ambient T was observed at high AV level compared with the other levels. Both RH and AV had no significant effects on respiration SHL or LHL. The cows lost more skin sensible heat and total respiration heat under long exposure than short exposure. When ambient T was below 20°C the total LHL (skin + respiration) represented approx. 50% of total heat loss, whereas above 28°C the LHL accounted for more than 70% of the total heat loss. Respiration heat loss increased by 34 and 24% under short and long exposures when ambient T rose from 16 to 32°C.

Risk-Based Screening Tools to Optimise HIV Testing Services: a Systematic Review.

PURPOSE OF REVIEW: Effective ways to diagnose the remaining people living with HIV who do not know their status are a global priority. We reviewed the use of risk-based tools, a set of criteria to identify individuals who would not otherwise be tested (screen in) or excluded people from testing (screen out). RECENT FINDINGS: Recent studies suggest that there may be value in risk-based tools to improve testing efficiency (i.e. identifying those who need to be tested). However, there has not been any systematic reviews to synthesize these studies. We identified 18,238 citations, and 71 were included. The risk-based tools identified were most commonly from high-income (51%) and low HIV (<5%) prevalence countries (73%). The majority were for "screening in" (70%), with the highest performance tools related to identifying MSM with acute HIV. Screening in tools may be helpful in settings where it is not feasible or recommended to offer testing routinely. Caution is needed for screening out tools, where there is a trade-off between reducing costs of testing with missing cases of people living with HIV.

Anatomy of Spinal Venous Drainage for the Neurointerventionalist: From Puncture Site to Intervertebral Foramen.

CSF-venous fistula is a relatively novel entity that is increasingly being recognized as a cause for spontaneous intracranial hypotension. Recently, our group published the first series of transvenous embolization of CSF-venous fistulas in this journal. Having now performed the procedure in 60 patients, we have garnered increasing familiarity with the anatomy and how to navigate our way through the venous system to any intervertebral foramen in the cervical, thoracic, and lumbar spine. The first part of this review summarizes the organization of spinal venous drainage as described in classic anatomy and interventional radiology texts, the same works that we studied when attempting our first cases. In the second part, we draw mostly on our own experience to provide a practical roadmap from the puncture site to the foramen. On the basis of these 2 parts, we hope this article will serve to collate the relevant anatomic knowledge and give confidence to colleagues who wish to embark on transvenous spinal procedures.

Effects of increasing air temperature on physiological and productive responses of dairy cows at different relative humidity and air velocity levels.

This study determined the effects of increasing ambient temperature (T) at different relative humidity (RH) and air velocity (AV) levels on the physiological and productive responses of dairy cows. Twenty Holstein dairy cows were housed inside climate-controlled respiration chambers, in which the climate was programmed to follow a daily pattern of lower night and higher day T with a 9°C difference, excluding effects from sun radiation. Within our 8-d data collection period, T was gradually increased from 7 to 21°C during the night (12 h) and 16 to 30°C during the day (12 h), with an incremental change of 2°C per day for both nighttime and daytime T. During each research period, RH and AV were kept constant at 1 of 5 treatment levels. A diurnal pattern for RH was created, with lower levels during the day and higher levels during the night: low (RH_l: 30-50%), medium (RH_m: 45-70%), and high (RH_h: 60-90%). The effects of AV were studied during the day at 3 levels: no fan (AV_l: 0.1 m/s), fan at medium speed (AV_m: 1.0 m/s), and fan at high speed (AV_h: 1.5 m/s). Effects of short and long exposure time to increasing T were evaluated by collecting data 2 times a day: in the morning [short: 1 h (or less) - exposure time] and afternoon (long: 8 h - exposure time). The animals had free access to feed and water and both were ad libitum. Respiration rate (RR), rectal temperature (RT), skin temperature (ST), dry matter intake, water intake, milk yield, and composition were measured. The inflection point temperatures (IPt) at which a certain variable started to change were determined for the different RH and AV levels and different exposure times. Results showed that IPt under long exposure time for RR (first indicator) varied between 18.9 and 25.5°C but was between 20.1 and 25.9°C for RT (a delayed indicator). The IPt for both RR and RT decreased with higher RH levels, whereas IPt increased with higher AV for RR but gave a minor change for RT. The ST was positively correlated with ambient T and ST was not affected by RH but significantly affected by AV. For RR, all IPt was lower under long exposure time than under short exposure time. The combination of higher RH levels and low AV level negatively affected dry matter intake. Water intake increased under all treatments except RH_l-AV_l. Treatment RH_h-AV_l negatively affected milk protein and fat yield, whereas treatments RH_m-AV_m and RH_m-AV_h reduced milk fat yield. We concluded that RH and AV significantly affected the responses of RR, RT, ST, and productive performance of high-producing Holstein cows. These responses already occurred at moderate ambient T of 19 to 26°C.

Hydrothermally synthesized nanostructured LiMnxFe1-xPO4 (x = 0-0.3) cathode materials with enhanced properties for lithium-ion batteries.

Nanostructured cathode materials based on Mn-doped olivine LiMnxFe1-xPO4 (x = 0, 0.1, 0.2, and 0.3) were successfully synthesized via a hydrothermal route. The field-emission scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) analyzed results indicated that the synthesized LiMnxFe1-xPO4 (x = 0, 0.1, 0.2, and 0.3) samples possessed a sphere-like nanostructure and a relatively homogeneous size distribution in the range of 100-200 nm. Electrochemical experiments and analysis showed that the Mn doping increased the redox potential and boosted the capacity. While the undoped olivine (LiFePO4) had a capacity of 169 mAh g-1 with a slight reduction (10%) in the initial capacity after 50 cycles (150 mAh g-1), the Mn-doped olivine samples (LiMnxFe1-xPO4) demonstrated reliable cycling tests with negligible capacity loss, reaching 151, 147, and 157 mAh g-1 for x = 0.1, 0.2, and 0.3, respectively. The results from electrochemical impedance spectroscopy (EIS) accompanied by the galvanostatic intermittent titration technique (GITT) have resulted that the Mn substitution for Fe promoted the charge transfer process and hence the rapid Li transport. These findings indicate that the LiMnxFe1-xPO4 nanostructures are promising cathode materials for lithium ion battery applications.

In situ synthesis of gold nanoparticles on novel nanocomposite lactose/alginate: Recyclable catalysis and colorimetric detection of Fe(III).

This work presents a simply new method for in situ synthesis of gold nanoparticles (AuNPs) using the biodegradable polysaccharides. A novel composite of lactose/alginate (Lac/Alg) could be prepared easily through ionotropic gelation mechanism which can reduce in situ gold ions into AuNPs. Lactose plays a crucial role as a reducing reagent which are demonstrated by FTIR analysis. The crystalline structure of AuNPs with a mean size of 10 nm has been confirmed by analysis techniques. The nanocomposite powder possesses highly catalytic performance for degradation of contaminants including 4-nitrophenol, methyl orange, rhodamine 6 G and rhodamine B. The dispersion solution of AuNPs@Lac/Alg was used as an effective probe for highly selective detection of Fe3+ ions. The detection mechanism replies on the aggregation of nanocomposite in the presence of Fe3+ ions. LOD value was found to be 0.8 µM in a linear range of 2.0-80.0 µM.

Colorectal Cancer Related to Chronic Strongyloides stercoralis Infection.

The majority of individuals with Strongyloides stercoralis (S. stercoralis) colitis are clinically asymptomatic. Symptomatic individuals may complain of nonspecific gastrointestinal symptoms, such as abdominal pain, intermittent or persistent diarrhea, nausea, or loss of appetite. In addition, skin manifestations such as recurrent urticaria can occur. If infection is not diagnosed and left untreated, it can lead to chronic inflammation of the gastrointestinal tract. It is well documented that chronic colitis such as inflammatory bowel disease can predispose individuals to colorectal cancer. Additionally, there is evidence of chronic parasitic infections inducing the development of cancers in other organs within the gastrointestinal tract. In this case vignette, we describe a case of chronic Strongyloides stercoralis infection in a Peruvian woman presenting with colorectal cancer.

An evidence-based strategy to screen for pulmonary arterial hypertension in systemic sclerosis.

BACKGROUND: Clinical practice guidelines recommend screening all systemic sclerosis (SSc) patients for pulmonary arterial hypertension (PAH) with yearly echocardiograms. There is a paucity of evidence to support these guidelines. RESEARCH QUESTION: Can a prediction model identify SSc patients with a very low probability of PAH and therefore not requiring annual screening echocardiogram? STUDY DESIGN AND METHODS: We performed a case-control study of 925 unselected SSc subjects nested in a multi-centered, longitudinal cohort. The probability of PAH for each subject was calculated using the results of multivariate logistic regression models. A cut-off was identified for the estimated probability of PAH below which no subject developed PAH (100% sensitivity). RESULTS: Study subjects were predominantly female (87.5%), with mean (SD) age 58.6 (11.7) years and disease duration of 18.2 (12.2) years. Thirty-seven subjects developed PAH during 5407.97 person-years of observation (incidence rate 0.68 per 100 person-years). Shortness of breath (SOB), diffusing capacity for carbon monoxide (DLCO) and NT-proBNP were independent predictors of PAH. All SSc-PAH cases had a probability of PAH of >1.1%. Subjects below this cut-off, none of whom had PAH, accounted for 46.2% of the study population. INTERPRETATION: A simple prediction model identified subjects at very low probability of PAH who could potentially forego annual screening echocardiogram. This represents almost half of SSc subjects in a general SSc population. This study, which is the first evidence-based study for the rational use of follow-up echocardiograms in an unselected SSc cohort, requires validation. The scoring system is freely available online at http://pahtool.ladydavis.ca.

TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Corpus Callosum.

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

The GALEN rhinosinusitis cohort: chronic rhinosinusitis with nasal polyps affects health-related quality of life.

BACKGROUND: Chronic rhinosinusitis (CRS) significantly affects health-related quality of life (HRQoL). Few multinational observational studies have evaluated the impact of CRS with nasal polyps (CRSwNP) on patients’ HRQoL. This study aimed to assess HRQoL outcomes (including analyses by disease severity and impact of comorbidities and refractory disease) in CRSwNP patients from a large European database. METHODOLOGY: Data were analysed from the Global Allergy and Asthma European Network (GALEN) Rhinosinusitis Cohort, including sociodemographic data, patient-reported disease severity (visual analogue scale), and scores on the 36-Item ShortForm Health Survey (SF-36) questionnaire. Differences in mean SF-36 scores were evaluated between patients with CRSwNP and population norms and between subgroups of interest (disease severity, comorbidity, and refractory disease, defined by a history of sinonasal surgery). RESULTS: Patients with CRSwNP (N = 445) had significantly lower mean SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores vs population norms, demonstrating that CRSwNP negatively affects HRQoL. The presence of comorbidities affected HRQoL, as shown by significant differences in PCS scores in patients with asthma or non-steroidal antiinflammatory drug-exacerbated respiratory disease, compared with patients without asthma. Patients with moderate-to-severe disease had significantly lower PCS scores than patients with mild disease. Severe disease had a significant impact on MCS score. History of surgery had a clinically meaningful negative effect on HRQoL compared with no history of surgery. CONCLUSIONS: CRSwNP patients have significantly lower HRQoL compared with population norms. The impact is greater in patients with greater disease severity, comorbidities, or refractory disease.

Role of JNK, MEK and adenylyl cyclase signalling in speed and directionality of enteric neural crest-derived cells.

BACKGROUND: Cells derived from the neural crest colonize the developing gut and give rise to the enteric nervous system. The rate at which the ENCC population advances along the bowel will be affected by both the speed and directionality of individual ENCCs. The aim of the study was to use time-lapse imaging and pharmacological activators and inhibitors to examine the role of several intracellular signalling pathways in both the speed and the directionality of individual enteric neural crest-derived cells in intact explants of E12.5 mouse gut. Drugs that activate or inhibit intracellular components proposed to be involved in GDNF-RET and EDN3-ETB signalling in ENCCs were used. FINDINGS: Pharmacological inhibition of JNK significantly reduced ENCC speed but did not affect ENCC directionality. MEK inhibition did not affect ENCC speed or directionality. Pharmacological activation of adenylyl cyclase or PKA (a downstream cAMP-dependent kinase) resulted in a significant decrease in ENCC speed and an increase in caudal directionality of ENCCs. In addition, adenylyl cyclase activation also resulted in reduced cell-cell contact between ENCCs, however this was not observed following PKA activation, suggesting that the effects of cAMP on adhesion are not mediated by PKA. CONCLUSIONS: JNK is required for normal ENCC migration speed, but not directionality, while cAMP signalling appears to regulate ENCC migration speed, directionality and adhesion. Collectively, our data demonstrate that intracellular signalling pathways can differentially affect the speed and directionality of migrating ENCCs.

Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.

The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.