Carbonate uranium isotopes record global expansion of marine anoxia during the Toarcian Oceanic Anoxic Event.

The Toarcian Oceanic Anoxic Event (T-OAE; ~183 Mya) was a globally significant carbon-cycle perturbation linked to widespread deposition of organic-rich sediments, massive volcanic CO2 release, marine faunal extinction, sea-level rise, a crisis in carbonate production related to ocean acidification, and elevated seawater temperatures. Despite recognition of the T-OAE as a potential analog for future ocean deoxygenation, current knowledge on the severity of global ocean anoxia is limited largely to studies of the trace element and isotopic composition of black shales, which are commonly affected by local processes. Here, we present the first carbonate-based uranium isotope (δ238U) record of the T-OAE from open marine platform limestones of the southeastern Tethys Ocean as a proxy for global seawater redox conditions. A significant negative δ238U excursion (~0.4‰) is recorded just prior to the onset of the negative carbon isotope excursion comprised within the T-OAE, followed by a long-lived recovery of δ238U values, thus confirming that the T-OAE represents a global expansion of marine anoxia. Using a Bayesian inverse isotopic mass balance model, we estimate that anoxic waters covered ~6 to 8% of the global seafloor during the peak of the T-OAE, which represents 28 to 38 times the extent of anoxia in the modern ocean. These data, combined with δ238U-based estimates of seafloor anoxic area for other CO2-driven Phanerozoic OAEs, suggest a common response of ocean anoxia to carbon release, thus improving prediction of future anthropogenically induced ocean deoxygenation.

The state of pelvic floor muscle dynamometry: A scoping review.

AIMS: To discuss the advantages and limitation of the different pelvic floor muscle (PFM) dynamometers available, both in research and industry, and to present the extent of variation between them in terms of structure, functioning, psychometric properties, and assessment procedures. METHODS: We identified relevant studies from four databases (MEDLINE, Compendex, Web of Science, and Derwent Innovations Index) up to December 2020 using terms related to dynamometry and PFM. In addition, we conducted a hand search of the bibliographies of all relevant reports. Peer-reviewed papers, conference proceedings, patents and user's manuals for commercial dynamometers were included and assessed by two independent reviewers. RESULTS: One hundred and one records were included and 23 PFM dynamometers from 15 research groups were identified. From these, 20 were considered as clinical dynamometers (meant for research settings) and three as personal dynamometers (developed by the industry). Overall, significant heterogeneity was found in their structure and functioning, which limits development of normative data for PFM force in women. Further research is needed to assess the psychometric properties of PFM dynamometers and to standardize assessment procedures. CONCLUSION: This review points up to the heterogeneity of existing dynamometers and methods of assessing PFM function. It highlights the need to better document their design and assessment protocol methods. Additionally, this review recommends standards for new dynamometers to allow the establishment of normalized data.

Radiation dose reduction with deep-learning image reconstruction for coronary computed tomography angiography.

OBJECTIVES: Deep-learning image reconstruction (DLIR) offers unique opportunities for reducing image noise without degrading image quality or diagnostic accuracy in coronary CT angiography (CCTA). The present study aimed at exploiting the capabilities of DLIR to reduce radiation dose and assess its impact on stenosis severity, plaque composition analysis, and plaque volume quantification. METHODS: This prospective study includes 50 patients who underwent two sequential CCTA scans at normal-dose (ND) and lower-dose (LD). ND scans were reconstructed with Adaptive Statistical Iterative Reconstruction-Veo (ASiR-V) 100%, and LD scans with DLIR. Image noise (in Hounsfield units, HU) and quantitative plaque volumes (in mm3) were assessed quantitatively. Stenosis severity was visually categorized into no stenosis (0%), stenosis (< 20%, 20-50%, 51-70%, 71-90%, 91-99%), and occlusion (100%). Plaque composition was classified as calcified, non-calcified, or mixed. RESULTS: Reduction of radiation dose from ND scans with ASiR-V 100% to LD scans with DLIR at the highest level (DLIR-H; 1.4 mSv vs. 0.8 mSv, p < 0.001) had no impact on image noise (28 vs. 27 HU, p = 0.598). Reliability of stenosis severity and plaque composition was excellent between ND scans with ASiR-V 100% and LD scans with DLIR-H (intraclass correlation coefficients of 0.995 and 0.974, respectively). Comparison of plaque volumes using Bland-Altman analysis revealed a mean difference of - 0.8 mm3 (± 2.5 mm3) and limits of agreement between - 5.8 and + 4.1 mm3. CONCLUSION: DLIR enables a reduction in radiation dose from CCTA by 43% without significant impact on image noise, stenosis severity, plaque composition, and quantitative plaque volume. KEY POINTS: •Deep-learning image reconstruction (DLIR) enables radiation dose reduction by over 40% for coronary computed tomography angiography (CCTA). •Image noise remains unchanged between a normal-dose CCTA reconstructed by ASiR-V and a lower-dose CCTA reconstructed by DLIR. •There is no impact on the assessment of stenosis severity, plaque composition, and quantitative plaque volume between the two scans.

Spinal pain and major depression in a military cohort: bias analysis of dependent misclassification in electronic medical records.

BACKGROUND: Spinal pain and major depression are prevalent conditions in adult populations and are particularly impactful in the military. However, the temporal relationship between these two conditions remains poorly understood. METHODS: Using data extracted from electronic medical records, we assessed the association between incident diagnoses of spinal pain and major depression in a cohort of 48,007 Canadian Armed Forces personnel followed from January 2017 to August 2018. We used multivariate Poisson regression to measure the association between the period prevalence of these two conditions. We used probabilistic bias modelling to correct our estimates for misclassification of spinal pain and major depression. RESULTS: After correcting for misclassification with probabilistic bias modelling, subjects newly diagnosed with spinal pain during the study period were 1.41 times (95% interval 1.25, 1.59) more likely also to be diagnosed with incident major depression, and personnel newly diagnosed with major depression were 1.28 times (95% interval 1.17, 1.39) more likely also to be diagnosed with spinal pain, compared to undiagnosed counterparts of the same age and sex. Without bias corrections, we would have overestimated the magnitude of the association between major depression and spinal pain by a factor of approximately 2.0. CONCLUSION: Our results highlight a moderate and bi-directional association between two of the most prevalent disorders in military populations. Our results also highlight the importance of correcting for misclassification in electronic medical record data research.

Diversity of Dromedary Camel Coronavirus HKU23 in African Camels Revealed Multiple Recombination Events among Closely Related Betacoronaviruses of the Subgenus Embecovirus.

Genetic recombination has frequently been observed in coronaviruses. Here, we sequenced multiple complete genomes of dromedary camel coronavirus HKU23 (DcCoV-HKU23) from Nigeria, Morocco, and Ethiopia and identified several genomic positions indicative of cross-species virus recombination events among other betacoronaviruses of the subgenus Embecovirus (clade A beta-CoVs). Recombinant fragments of a rabbit coronavirus (RbCoV-HKU14) were identified at the hemagglutinin esterase gene position. Homolog fragments of a rodent CoV were also observed at 8.9-kDa open reading frame 4a at the 3' end of the spike gene. The patterns of recombination differed geographically across the African region, highlighting a mosaic structure of DcCoV-HKU23 genomes circulating in dromedaries. Our results highlighted active recombination of coronaviruses circulating in dromedaries and are also relevant to the emergence and evolution of other betacoronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV).IMPORTANCE Genetic recombination is often demonstrated in coronaviruses and can result in host range expansion or alteration in tissue tropism. Here, we showed interspecies events of recombination of an endemic dromedary camel coronavirus, HKU23, with other clade A betacoronaviruses. Our results supported the possibility that the zoonotic pathogen MERS-CoV, which also cocirculates in the same camel species, may have undergone similar recombination events facilitating its emergence or may do so in its future evolution.

Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study).

PURPOSE: To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD). DESIGN: A phase 4 randomized, partially masked, multicenter study. PARTICIPANTS: Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more. METHODS: Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections. MAIN OUTCOME MEASURES: The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24. RESULTS: Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups. CONCLUSIONS: No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.

Candida albicans Mrv8, is involved in epithelial damage and biofilm formation.

Candida albicans is the most common human fungal pathogen that can cause superficial and deep-seated infections in susceptible individuals. Despite its medical importance, the vast majority of C. albicans genes remain of unknown function. Here, we report a role for the lineage-specific gene, MRV8, in host pathogen interactions, mycelial microcolony maturation and biofilm formation. In silico analysis indicated that MRV8 encodes a four-pass transmembrane protein unique to the closely related pathogens C. albicans and Candida dubliniensis. Deletion of MRV8 did not affect C. albicans adherence to, or initial invasion into human oral epithelia, but inhibited mycelial development and strongly reduced epithelial damage. mrv8Δ/Δ cells exhibited a media-dependent defect in biofilm formation and mutant biofilm metabolic activity was enhanced by cyclosporin A. mrv8Δ/Δ biofilms were more tolerant to treatment with caspofungin, but not to fluconazole or amphotericin B. Co-stimulation with calcium chloride and calcofluor white rescued biofilm growth in the presence of caspofungin, and this rescue-effect was Mrv8-dependent. Together, our data demonstrate an important role for a lineage-specific gene (MRV8) in C. albicans biofilm formation, drug tolerance and host-pathogen interactions.

Incidence of major depression diagnoses in the Canadian Armed Forces: longitudinal analysis of clinical and health administrative data.

PURPOSE: Major depression is a leading cause of morbidity in military populations. However, due to a lack of longitudinal data, little is known about the rate at which military personnel experience the onset of new episodes of major depression. We used a new source of clinical and administrative data to estimate the incidence of major depression diagnoses in Canadian Armed Forces (CAF) personnel, and to compare incidence rates between demographic and occupational factors. METHODS: We extracted all data recorded in the electronic medical records of CAF Regular Force personnel, at every primary care and mental health clinical encounter since 2016. Using a 12-month lookback period, we linked data over time, and identified all patients with incident diagnoses of major depression. We then linked clinical data to CAF administrative records, and estimated incidence rates. We used multivariate Poisson regression to compare adjusted incidence rates between demographic and occupational factors. RESULTS: From January to December 2017, CAF Regular Force personnel were diagnosed with major depression at a rate of 29.2 new cases per 1000 person-years at risk. Female sex, age 30 years and older, and non-officer ranks were associated with significantly higher incidence rates. CONCLUSIONS: We completed the largest study to date on diagnoses of major depression in the Canadian military, and have provided the first estimates of incidence rates in CAF personnel. Our results can inform future mental health resource allocation, and ongoing major depression prevention efforts within the Canadian Armed Forces and other military organizations.

Mental Health Service Utilization in Depressed Canadian Armed Forces Personnel.

BACKGROUND: Major depression is prevalent, impactful, and treatable in military populations, but not all depressed personnel seek professional care in a given year. Care-seeking patterns (including the use of primary vs. specialty care) and factors associated with the likelihood of mental health service utilization in depressed military personnel are poorly understood. METHODS: Our sample included 520 Regular Force respondents to the 2013 Canadian Forces Mental Health Survey. All study participants had past-year major depression. Subjects reported whether they had spoken about their mental health with at least one health professional in the past 12 months. We used multivariate Poisson regression to explore factors associated with past-year mental health service use. RESULTS: Three-quarters of Canadian military personnel with past-year depression had sought mental health care in the previous 12 months. Among care-seeking personnel, 70% had seen a psychologist or psychiatrist, while 5% had exclusively received care from a primary care physician. Belief in the effectiveness of mental health care was the factor most strongly associated with care seeking. Female gender, functional impairments, and psychiatric comorbidities were also associated with care seeking. Surprisingly, stigma perceptions had no independent association with care seeking. CONCLUSIONS: The proportion of depressed Canadian Armed Forces personnel who seek professional care and who access specialty mental health care is higher than in most other populations. However, an important minority of patients are not accessing health services. Efforts to further increase mental health service utilization in the Canadian military should continue to target beliefs about the effectiveness of mental health care.

SciPhon: a data analysis software for nuclear resonant inelastic X-ray scattering with applications to Fe, Kr, Sn, Eu and Dy.

The synchrotron radiation technique of nuclear resonant inelastic X-ray scattering (NRIXS), also known as nuclear resonance vibrational spectroscopy or nuclear inelastic scattering, provides a wealth of information on the vibrational properties of solids. It has found applications in studies of lattice dynamics and elasticity, superconductivity, heme biochemistry, seismology, isotope geochemistry and many other fields. It involves probing the vibrational modes of solids by using the nuclear resonance of Mössbauer isotopes such as 57Fe, 83Kr, 119Sn, 151Eu and 161Dy. After data reduction, it provides the partial phonon density of states of the Mössbauer isotope that is investigated, as well as many other derived quantities such as the mean force constant of the chemical bonds and the Debye velocity. The data reduction is, however, not straightforward and involves removal of the elastic peak, normalization and Fourier-Log transformation. Furthermore, some of the quantities derived are highly sensitive to details in the baseline correction. A software package and several novel procedures to streamline and hopefully improve the reduction of the NRIXS data generated at sector 3ID of the Advanced Photon Source have been developed. The graphical user interface software is named SciPhon and runs as a Mathematica package. It is easily portable to other platforms and can be easily adapted for reducing data generated at other beamlines. Several tests and comparisons are presented that demonstrate the usefulness of this software, whose results have already been used in several publications. Here, the SciPhon software is used to reduce Kr, Sn, Eu and Dy NRIXS data, and potential implications for interpreting natural isotopic variations in those systems are discussed.

Understanding the Parent Perspective on Prenatal Consultation for Fetuses with Congenital Anomalies.

INTRODUCTION: An increasing number of congenital anomalies are diagnosed prenatally. Understanding the implications of these diagnoses on the life of their child is critical for parents, and the surgical consultation is often the primary venue for this education. Little is known about the parent perspective on prenatal consultation. METHODS: Parents undergoing prenatal consultation were identified and in-depth interviews were conducted to explore the following: understanding of the diagnosis, preparedness for postnatal course, and suggestions for improvement. Qualitative analysis was performed to generate themes. RESULTS: Twelve interviews with 16 family members were performed, encompassing a variety of prenatal diagnoses and outcomes. Near-ubiquitous emotions included fear, anxiety, and self-blame. Surgical consultation relieved anxiety for some, but the uncertain outcome increased anxiety in others. Most were satisfied with the information communicated during the encounter; however, those with worse outcomes wished they were better warned. Parents emphasized the importance of support systems and educational materials. CONCLUSIONS: Parents appreciate learning about all potential outcomes for the fetus, even though this generates anxiety. Surgeons should discuss the range of possible outcomes while acknowledging that uncertainty leads to anxiety. It is essential to incorporate the parent perspective when conducting prenatal consultation and training pediatric surgeons in this important practice.

Alteration of the Copper-Binding Capacity of Iron-Rich Humic Colloids during Transport from Peatland to Marine Waters.

Blanket bogs contain vast amounts of Sphagnum-derived organic substances which can act as powerful chelators for dissolved iron and thus enhance its export to the coastal ocean. To investigate the variations in quantity and quality of these exports, adsorptive cathodic stripping voltammetry (CSV) was used to characterize the metal binding properties of molecular weight-fractionated dissolved organic matter (MW-fractionated DOM) in the catchment and coastal plume of a small peat-draining river over a seasonal cycle. Within the plume, both iron- and copper-binding organic ligands showed a linear, conservative distribution with increasing salinity, illustrating the high stability of peatland-derived humic substances (HS). Within the catchment, humic colloids lost up to 50% of their copper-binding capacity, expressed as a molar ratio to organic carbon, after residing for 1 week or more in the main reservoir of the catchment. Immediately downstream of the reservoir, the molar ratio [L2]/[Corg], where L2 was the second strongest copper-binding ligand, was 0.75 × 10-4 when the reservoir residence time was 5 h but 0.34 × 10-4 when it was 25 days. Residence time did not affect the carbon specific iron-binding capacity of the humic substances which was [L]/[Corg] = (0.80 ± 0.20) × 10-2. Our results suggest that the loss of copper-binding capacity with increasing residence time is caused by intracolloidal interactions between iron and HS during transit from peat soil to river mouth.

Morphometric Analysis of Explant Lungs in Cystic Fibrosis.

RATIONALE: After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking. OBJECTIVES: To quantify the involvement of small and large airways in end-stage CF. METHODS: Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology. MEASUREMENTS AND MAIN RESULTS: On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution. CONCLUSIONS: Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.

Awareness of treatment history in family and friends, and mental health care seeking propensity.

PURPOSE: Many adults suffering from mental disorders never receive the care they need. The role of family and friends in overcoming mental health treatment barriers is poorly understood. We investigated the association between awareness of lifetime mental health treatment history in one's family or friends, and likelihood of having recently received mental health care for oneself. METHODS: Using Canadian Community Health Survey 2012-Mental Health data, we defined care seekers as individuals who talked about mental health issues to at least one health professional in the past 12 months. Seekers were matched to non-seekers based on estimated care seeking propensity, and 1933 matched pairs were created. Reported awareness of lifetime treatment history in family and friends was compared between seekers and non-seekers. RESULTS: There were no differences in the distribution of any confounder of interest between seekers and non-seekers. 73% of seekers were aware of treatment history in family or friends, compared to only 56% of non-seekers (RR 1.3; 95% CI 1.2, 1.3). Awareness of treatment history in family members had nearly identical associations with care seeking as awareness of treatment history in friends. CONCLUSIONS: We have found a social clustering of mental health care seeking behavior; individuals who were aware of lifetime treatment history in family or friends were more likely to have recently sought care for themselves. These novel results are consistent with a social learning model of care seeking behavior, and could inform efforts to bridge the current mental health treatment gap.

Half of 23 Belgian dog breeds has a compromised genetic diversity, as revealed by genealogical and molecular data analysis.

The genetic diversity in 23 dog breeds raised in Belgium was investigated using both genealogical analysis and microsatellite markers. Some of these breeds are native breeds, with only small populations maintained. Pedigree and molecular data, obtained from the Belgian kennel club, were used to calculate the inbreeding coefficients, realised effective population size as well as probabilities of gene origin and average observed heterozygosity. Inbreeding coefficients ranged from 0.8 to 44.7% and realised effective population size varied between 3.2 and 829.1, according to the used method and breed. Mean observed heterozygosity ranged from 0.47 to 0.73. Both pedigree and molecular methods reveal low genetic diversity and presence of bottlenecks, especially in native Belgian breeds with small population sizes. Furthermore, principal component analysis on the set of investigated diversity parameters revealed no groups of breeds that could be identified in which similar breeding strategies could be applied to maintain genetic diversity.

Lung structure-function correlation in patients with primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disease, characterised by chronic airway infection. In cystic fibrosis, FEV1 is insensitive to detect patients with structural damage, and Lung Clearance Index (LCI) was proposed as a better marker of early lung damage. In PCD, the relationship between functional and structural abnormalities has been less studied. We aimed to re-examine this in a cohort of children and adults with mild to moderate PCD. METHODS: Thirty-eight patients with PCD (5.2-25.0 years) and 70 healthy controls (4.4-25.8 years) were recruited to compare LCI, measured by N2 multiple breath washout and FEV1 in a prospective observational trial. In a subset of 30 patients who underwent chest imaging, structural abnormalities were evaluated with cystic fibrosis computed tomography (CFCT) scores. RESULTS: LCI was abnormal in 28 of 38 patients and a moderate correlation was observed between LCI and FEV1 (r=-0.519, p=0.001). Moreover, LCI correlated well with CFCT total score (r=0.800, p<0.001) and also with subscores for airway wall thickening (r=0.809, p<0.001), mucus plugging (r=0.720, p<0.001) and bronchiectasis (r=0.494, p<0.001). Concordance was seen between LCI and CFCT in 25 of 30 (83%) patients, but between FEV1 and CFCT in only 16 of 30 (53%) patients. LCI was more sensitive (90.9%, 95% CI 70.8 to 98.6) to detect patients with structural abnormalities than FEV1 (36.4%, 95% CI 17.2 to 59.3). CONCLUSIONS: We demonstrated that measuring LCI in patients with PCD is of clinical relevance; it was more frequently abnormal than FEV1, correlated well with CFCT and was more sensitive than FEV1 to detect patients with structural abnormalities.

Distinct roles of Candida albicans-specific genes in host-pathogen interactions.

Human fungal pathogens are distributed throughout their kingdom, suggesting that pathogenic potential evolved independently. Candida albicans is the most virulent member of the CUG clade of yeasts and a common cause of both superficial and invasive infections. We therefore hypothesized that C. albicans possesses distinct pathogenicity mechanisms. In silico genome subtraction and comparative transcriptional analysis identified a total of 65 C. albicans-specific genes (ASGs) expressed during infection. Phenotypic characterization of six ASG-null mutants demonstrated that these genes are dispensable for in vitro growth but play defined roles in host-pathogen interactions. Based on these analyses, we investigated two ASGs in greater detail. An orf19.6688Δ mutant was found to be fully virulent in a mouse model of disseminated candidiasis and to induce higher levels of the proinflammatory cytokine interleukin-1ß (IL-1ß) following incubation with murine macrophages. A pga16Δ mutant, on the other hand, exhibited attenuated virulence. Moreover, we provide evidence that secondary filamentation events (multiple hyphae emerging from a mother cell and hyphal branching) contribute to pathogenicity: PGA16 deletion did not influence primary hypha formation or extension following contact with epithelial cells; however, multiple hyphae and hyphal branching were strongly reduced. Significantly, these hyphae failed to damage host cells as effectively as the multiple hypha structures formed by wild-type C. albicans cells. Together, our data show that species-specific genes of a eukaryotic pathogen can play important roles in pathogenicity.

Sustaining a hygiene education intervention to prevent and control geohelminth infections at schools in the Peruvian Amazon.

The World Health Organization currently recommends that school-based deworming programs include health hygiene education as a complementary measure. However, the sustainability and long-term impact of such hygiene education had yet to be assessed. In July 2012, this cross-sectional study was conducted in 18 primary schools in the Peruvian Amazon to gauge continuing adherence to a health hygiene education intervention introduced 2 years earlier to reduce soil-transmitted helminth infections. Due in large part to high teacher turn-over, only 9 of 47 (19.1%) teachers were still implementing the intervention. Health hygiene education interventions must, therefore, be designed to ensure sustainability in order to contribute to the overall effectiveness of school-based deworming programs.

The novel Candida albicans transporter Dur31 Is a multi-stage pathogenicity factor.

Candida albicans is the most frequent cause of oral fungal infections. However, the exact pathogenicity mechanisms that this fungus employs are largely unknown and many of the genes expressed during oral infection are uncharacterized. In this study we sought to functionally characterize 12 previously unknown function genes associated with oral candidiasis. We generated homozygous knockout mutants for all 12 genes and analyzed their interaction with human oral epithelium in vitro. Eleven mutants caused significantly less epithelial damage and, of these, deletion of orf19.6656 (DUR31) elicited the strongest reduction in pathogenicity. Interestingly, DUR31 was not only involved in oral epithelial damage, but in multiple stages of candidiasis, including surviving attack by human neutrophils, endothelial damage and virulence in vivo. In silico analysis indicated that DUR31 encodes a sodium/substrate symporter with 13 transmembrane domains and no human homologue. We provide evidence that Dur31 transports histatin 5. This is one of the very first examples of microbial driven import of this highly cytotoxic antimicrobial peptide. Also, in contrast to wild type C. albicans, dur31Δ/Δ was unable to actively increase local environmental pH, suggesting that Dur31 lies in the extracellular alkalinization hyphal auto-induction pathway; and, indeed, DUR31 was required for morphogenesis. In agreement with this observation, dur31Δ/Δ was unable to assimilate the polyamine spermidine.

Diagnostic accuracy of nitric oxide measurements to detect primary ciliary dyskinesia.

BACKGROUND: Primary Ciliary Dyskinesia (PCD) is an orphan disease characterized by recurrent respiratory infections and an increased prevalence of situs inversus and male infertility. Low nasal Nitric Oxide (nNO) is used as a new test to diagnose PCD. The test sensitivity is good, but specificity has not been studied widely. Therefore, we evaluated the diagnostic accuracy of low nNO to diagnose PCD in a large cohort, including healthy patients and different disease controls. MATERIALS AND METHODS: Nasal nitric oxide was measured during plateau exhalation against resistance (nNOplat) and during tidal breathing (nNOtid). Moreover, we measured fractional exhaled NO (FENO). We included 226 patients: 38 with PCD, 49 healthy controls, and 139 disease controls (cystic fibrosis, humoral immunodeficiency, and asthma). RESULTS: The nNOplat cut-off value of 300 ppb provided the best sensitivity (89·5%) and specificity (87·3%) to detect PCD. There was overlap between PCD and disease controls: 16·5% of disease controls had a false-positive result. nNOtid correlated with nNOplat (r=0·912), but values differed (P=0·0001). The nNOtid cut-off of 200 ppb had a sensitivity of 89·5% and a specificity of 80·6% to detect PCD. The FENO cut-off of 10 ppb had an acceptable sensitivity (89·5%), but a low specificity (58·3%). Positive and negative likelihood ratios were suboptimal for all tests. CONCLUSIONS: nNOplat, nNOtid and FENO measurements overlap between PCD and disease controls. Sensitivity is comparable for the three tests. Applying composite scores slightly improves diagnostic accuracy. Given the less than 90% test sensitivity, PCD should be considered in patients with intermediate results.