Characterizing HIV transmission networks across the United States.
Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk. HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000-2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks ("clusters") were defined as ≥2 sequences with ≤1.5% genetic distance. Clusters including ≥3 patients ("networks") were evaluated for clinical and demographic associations. Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals ("dyads"), 54 clusters that included 3-14 individuals ("networks"), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10,000-100,000 copies/mL (P < .001) or >100,000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001). Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.


Predicting tissue-specific expressions based on sequence characteristics.
In multicellular organisms, including humans, understanding expression specificity at the tissue level is essential for interpreting protein function, such as tissue differentiation. We developed a prediction approach via generated sequence features from overrepresented patterns in housekeeping (HK) and tissue-specific (TS) genes to classify TS expression in humans. Using TS domains and transcriptional factor binding sites (TFBSs), sequence characteristics were used as indices of expressed tissues in a Random Forest algorithm by scoring exclusive patterns considering the biological intuition; TFBSs regulate gene expression, and the domains reflect the functional specificity of a TS gene. Our proposed approach displayed better performance than previous attempts and was validated using computational and experimental methods.


Totally videoendoscopic descending thoracic aorta-to-femoral artery bypass.
Descending thoracic aorta to femoral artery bypass is an effective and safe procedure for the treatment of aortoiliac occlusive disease when an approach to the abdominal aorta is undesirable. The major limitation of this technique has resulted from the morbidity rate associated with thoracotomy in a relatively high-risk vascular surgery population. As a minimally invasive procedure, videoendoscopy has been shown to improve the patient postoperative course and comfort in the field of general and thoracic surgery. The same benefits could be expected from a videoendoscopic surgery involving the thoracic aorta. In 2003 we reported the first case of a totally videoendoscopic descending thoracic aorta-to-femoral artery bypass procedure. In this article we report our additional experience with and the modifications we have made to this technique.


Bacteriocin (Marcescin) typing of clinical isolates of Serratia marcescens.
A simple, reproducible technique is described for bacteriocin typing of clinical isolates of Serratia marcescens. With 10 marcescin-producer strains, a total of 46 of 50 isolates (92%) of S. marcescens could be typed and categorized into 16 provisional types according to their sensitivity or tolerance to marcescins. The potential significance of this procedure with regard to delineation of outbreaks of nosocomial infection is discussed on the basis of preliminary epidemiological data.


Assessment of antenatal anxiety, depression and obsessive-compulsive disorder in pregnant women in the COVID-19 era.
To assess the mental health of pregnant women, with reference to anxiety, depression and obsessive-compulsive (OC) symptoms, during the COVID-19 pandemic. A cross-sectional survey was conducted in Ireland during the third wave of the pandemic between February and March 2021. Psychiatric, social and obstetric information was collected from pregnant women in a Dublin maternity hospital, alongside self-reported measures of mental health status. Of 392 women responding, 23.7% had anxiety, scoring >9 for GAD-7 (7-item generalised anxiety disorder), 20.4% had depression, scoring >9 for PHQ-9 (9-item depression screening tool: Patient health questionnaire) and 10.3% had obsessive-compulsive disorder (OCD), scoring >13 for Yale-Brown obsessive-compulsive scale symptom checklist (Y-BOCS). Amongst self-reported OCD symptoms, there was a preponderance for obsessions rather than compulsions. Of 392 women, 36.2% described their mental health as worse during the pandemic, most frequently describing symptoms of anxiety and sleep disturbance. When analysed against test scores, self-reported worsening of mental health was significantly associated with higher scores on the GAD-7, PHQ-9 and Y-BOCS scales. The three scores were positively interrelated. Poor mental health scores were associated with self-reported strain in relationship with the baby's father, and current or previous history of mental illness. This study found high levels of depression, anxiety and OC symptoms amongst pregnant women during COVID-19. This highlights the vulnerability of this group to mental illness and the importance of enhanced screening and support during pandemics.


Quiescence in Artemia franciscana embryos: reversible arrest of metabolism and gene expression at low oxygen levels.
Depression of the production and consumption of cellular energy appears to be a prerequisite for the survival of prolonged bouts of anoxia. A correlation exists between the degree of metabolic depression under anoxia and the duration of anoxia tolerance. In the case of brine shrimp (Artemia franciscana) embryos, oxygen deprivation induces a reversible quiescent state that can be tolerated for several years with substantial survivorship. A global arrest of cytoplasmic translation accompanies the transition into anoxia, and rates of protein synthesis in mitochondria from these embryos appears to be markedly reduced in response to anoxia. Previous evidence suggests that the acute acidification of intracellular pH (pHi) by over 1.0 unit during the transition into anoxia contributes to the depression of biosynthesis, but message limitation does not appear to play a role in the down-regulation in either cellular compartment. The ontogenetic increase in mRNA levels for a mitochondrial-encoded subunit of cytochrome c oxidase (COX I) and for nuclear-encoded actin is blocked by anoxia and aerobic acidosis (artificial quiescence imposed by intracellular acidification under aerobic conditions). Further, the levels of COX I and actin mRNA do not decline appreciably during 6 h bouts of quiescence, even though protein synthesis is acutely arrested across this same period. Thus, the constancy of mRNA levels during quiescence indicates that reduced protein synthesis is not caused by message limitation but, instead, is probably controlled at the translational level. This apparent stabilization of mRNA under anoxia is mirrored in an extension of protein half-life. The ubiquitin-dependent pathway for protein degradation is depressed under anoxia and aerobic acidosis, as judged by the acute drop in levels of ubiquitin-conjugated proteins. Mitochondrial protein synthesis is responsive to both acidification of pHi and removal of oxygen per se. Matrix pH declines in parallel with pHi, and evidence from experiments with nigericin indicates that mitochondrial protein synthesis is depressed directly by acidification of matrix pH. The oxygen dependency of organellar protein synthesis is not explained by blockage of the electron transport chain or by the increased redox state. Rather, this cyanide- and antimycin-insensitive, but hypoxia-sensitive, inhibitory signature for the arrest of protein synthesis suggests the presence of a molecular oxygen sensor within the mitochondrion.


[Antimicrobial sensitivity of Escherichia coli strains with K1 antigen isolated from pregnant women and newborns].
The aim of this study was comparison of the susceptibility to antibiotics of E. coli strains with K1 antigen (E. coli K1+) and non-K1 E. coli strains (E. coli K1-). This study included 67 of E. coli K1+ and 67 of E. coli K1- strains isolated in the time period from June to September of 2008 from pregnant women and newborns hospitalized at dr. J. Biziel University Hospital number 2 L. Rydygier Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń. Antimicrobial susceptibility of E. coli strains was tested by the disc-diffusion method, on the Mueller Hinton 2 Agar (Becton Dickinson). It was found that 64,2% of E. coli K1+ strains and 53,7% of E. coli K1-strains were susceptible to all tested antibiotics and chemioterapeutics. E. coli K1- strains were more often than E. coli K1+ nonsusceptible to at least one antimicrobial agent. The obtained results indicate that E. coli K1+ strains significant differed in the susceptibility to ampicillin/sulbactam (85,1% versus 95,5%) (p=0,041), cephalothin (70,1% versus 85,1%) (p=0,038) and tetracycline (91,0% versus 74,6%) (p=0,012) from E. coli K1-strains. All tested E. coli K1+ and K1-strains were sensitive to piperacillin/tazobactam, cefoperazone/sulbactam, cefotaxime, ceftazidime, cefepime, imipenem, amikacin, netilmicin and tigecycline. There weren't the ESBL-producing strains among tested E. coli K1+ and K1- rods.


Diagnosis of congenital Trypanosoma cruzi infection: A serologic test using Shed Acute Phase Antigen (SAPA) in mother-child binomial samples.
Chagas congenital infection is an important health problem in endemic and non-endemic areas in which Trypanosoma cruzi-infected women can transmit the parasite to their offspring. In this study, we evaluated the antibody levels against the T. cruzi Shed Acute Phase Antigen (SAPA) in 91 binomial samples of seropositive pregnant women and their infected and non-infected children by ELISA. In 70 children without congenital T. cruzi transmission, the titers of anti-SAPA antibodies were lower than those of their seropositive mothers. In contrast, 90.5% of 21 congenitally infected children, at around 1 month of age, showed higher anti-SAPA antibody levels than their mothers. Subtracting the SAPA-ELISA mother OD value to the SAPA-ELISA child OD allowed efficient detection of most T. cruzi congenitally infected children immediately after birth, when total anti-parasite antibodies transferred during pregnancy are still present in all children born to seropositive women. A positive correlation was observed between parasitemia levels in mothers and infants evaluated by quantitative DNA amplification and anti-SAPA antibody titers by ELISA. As SAPA serology has proved to be very efficient to detect T. cruzi infection in mother-child binomial samples, it could be of extreme help for early diagnosis of newborns, in maternities and hospitals where DNA amplification is not available. This prompt diagnosis may prevent drop out of the long-term follow-up for future diagnosis and may ensure early trypanocidal treatment, which has proved to be efficient to cure infants with congenital Chagas disease.


Chromatin structure of the Saccharomyces cerevisiae DNA topoisomerase I promoter in different growth phases.
We have determined the chromatin organization of the Saccharomyces cerevisiae DNA topoisomerase I promoter. Three nucleosomal core particles have been mapped at nucleotide level over the promoter region, encompassing the presumptive TATA sequence and the two RNA initiation sites; the most upstream nucleosome particle forms on to a 29 bp-long poly(dA-dT) element. This simple organization remains constant throughout both the logarithmic and the linear phase of growth, with the exception of an increased accessibility to micrococcal nuclease of the nucleosome covering the TATA box and the RNA initiation sites during the diauxic shift (the switching from the fermentative to the respiratory metabolism) in parallel with an increase of the DNA topoisomerase I mRNA. In addition, a strong disorganization of the bulk chromatin structure in the late stationary phase is also reported.


Quantitative analysis of collagen fiber organization in injured tendons using Fourier transform-second harmonic generation imaging.
Fourier transform-second harmonic generation (FT-SHG) imaging is used as a technique for evaluating collagenase-induced injury in horse tendons. The differences in collagen fiber organization between normal and injured tendon are quantified. Results indicate that the organization of collagen fibers is regularly oriented in normal tendons and randomly organized in injured tendons. This is further supported through the use of additional metrics, in particular, the number of dark (no/minimal signal) and isotropic (no preferred fiber orientation) regions in the images, and the ratio of forward-to-backward second-harmonic intensity. FT-SHG microscopy is also compared with the conventional polarized light microscopy and is shown to be more sensitive to assessing injured tendons than the latter. Moreover, sample preparation artifacts that affect the quantitative evaluation of collagen fiber organization can be circumvented by using FT-SHG microscopy. The technique has potential as an assessment tool for evaluating the impact of various injuries that affect collagen fiber organization.


CNAnova: a new approach for finding recurrent copy number abnormalities in cancer SNP microarray data.
The current generation of single nucleotide polymorphism (SNP) arrays allows measurement of copy number aberrations (CNAs) in cancer at more than one million locations in the genome in hundreds of tumour samples. Most research has focused on single-sample CNA discovery, the so-called segmentation problem. The availability of high-density, large sample-size SNP array datasets makes the identification of recurrent copy number changes in cancer, an important issue that can be addressed using the cross-sample information. We present a novel approach for finding regions of recurrent copy number aberrations, called CNAnova, from Affymetrix SNP 6.0 array data. The method derives its statistical properties from a control dataset composed of normal samples and, in contrast to previous methods, does not require segmentation and permutation steps. For rigorous testing of the algorithm and comparison to existing methods, we developed a simulation scheme that uses the noise distribution present in Affymetrix arrays. Application of the method to 128 acute lymphoblastic leukaemia samples shows that CNAnova achieves lower error rate than a popular alternative approach. We also describe an extension of the CNAnova framework to identify recurrent CNA regions with intra-tumour heterogeneity, present in either primary or relapsed samples from the same patients. The CNAnova package and synthetic datasets are available at http://www.compbio.group.cam.ac.uk/software.html.


Nifedipine and alpha 1-adrenergic blockade in Raynaud's phenomenon.
The efficacy of nifedipine and prazosin in the treatment of Raynaud's phenomenon was assessed in a prospective double-blind randomized cross-over trial in 15 patients. Each patient received one week of nifedipine 20 mg TID, one week of prazosin 1 mg TID, and 2 weeks of placebo. Nifedipine was shown to be effective in reducing both the frequency and the severity of Raynaud's phenomenon, whereas prazosin was ineffective. Before initiation of therapy in the 15 patients, pressor responses to the intravenous alpha 1-agonist phenylephrine were assessed in the basal state, 30 min after 20 mg oral nifedipine, and 30 min after 1 mg oral prazosin; the shift to the right of the log dose-vasopressor response curves to phenylephrine was similar with nifedipine and prazosin.


The provision and impact of online patient access to their electronic health records (EHR) and transactional services on the quality and safety of health care: systematic review protocol.
Innovators have piloted improvements in communication, changed patterns of practice and patient empowerment from online access to electronic health records (EHR). International studies of online services, such as prescription ordering, online appointment booking and secure communications with primary care, show good uptake of email consultations, accessing test results and booking appointments; when technologies and business process are in place. Online access and transactional services are due to be rolled out across England by 2015; this review seeks to explore the impact of online access to health records and other online services on the quality and safety of primary health care. To assess the factors that may affect the provision of online patient access to their EHR and transactional services, and the impact of such access on the quality and safety of health care. Two reviewers independently searched 11 international databases during the period 1999-2012. A range of papers including descriptive studies using qualitative or quantitative methods, hypothesis-testing studies and systematic reviews were included. A detailed eligibility criterion will be used to shape study inclusion. A team of experts will review these papers for eligibility, extract data using a customised extraction form and use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument to determine the quality of the evidence and the strengths of any recommendation. Data will then be descriptively summarised and thematically synthesised. Where feasible, we will perform a quantitative meta-analysis. Prospero (International Prospective Register of Systematic Reviews) registration number: crd42012003091.


The effect of expertise on memory conformity: a test of informational influence.
Conforming to erroneous memory reports of co-witnesses can have serious impacts on subsequent forensic investigation and court reports. One theoretical explanation proposed is that memory conformity arises due to informational influence; the co-witness desires to give accurate information and reports the co-witness's version because they perceive the co-witness as being more credible. We tested the idea that perceptions of credibility drive memory conformity. We manipulated credibility through expertise; specifically, by telling participants that the (confederate) co-witness had previously worked as either a policeman (high expertise) or an electrician (low expertise). After a discussion with the co-witness, we assessed cued-recall memory and perceptions of credibility about the co-witness and the self. We found that higher expertise led to greater memory conformity. Although higher expertise also led to higher credibility assessments of the co-witness, this was only for perceptions of the credibility as an eye-witness and memory confidence, neither of which predicted memory conformity. By contrast, memory accuracy of the co-witness relative to self-memory accuracy predicted memory conformity, but this was not affected by expertise. These results show support for an informational influence explanation but suggest that expertise perceptions operate differently from our explanation.


A risk model based on the tumor microenvironment to predict survival and immunotherapy efficacy for ovarian cancer.
Based on the interactions between immune components in the tumor microenvironment and ovarian cancer (OC) cells, immunotherapies have been demonstrated to be effective in dramatically increasing survival rates. This study aimed to identify landmark genes, develop a prognostic risk model, and explore its relevance to the efficacy of immunotherapy. A risk model was built based on the immune- and stromal-related genes, which were extracted from the OC gene expression data of "The Cancer Genome Atlas" (TCGA) database. Survival analysis and receiver operating characteristic (ROC) analysis were then conducted through the model's risk score pattern, which was established depending on the TCGA training cohort and verified based on the internal TCGA cohort and external "Gene Expression Omnibus" (GEO) datasets. Furthermore, the immune-related characteristics and prognostic values of the risk model were evaluated. The prognostic risk model for ovarian cancer demonstrated excellent performance in predicting survival rates, as validated in both the TCGA and GEO databases. The model showed significant associations with 17 functional immune cells, 17 immune checkpoints, PD-1, and several immune pathways, suggesting its potential to enhance the efficacy of immunotherapy in OC. The risk model developed in this study has the potential to serve as a prognostic marker for OC, enabling the development of personalized immunotherapy protocols and providing a theoretical basis for novel combinations of immunotherapeutic approaches.


Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial.
Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). To assess 1-year efficacy and safety of salsalate in T2DM. Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643). 3 private practices and 18 academic centers in the United States. Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes. 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures. The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.


Adaptive approaches to licensing, health technology assessment, and introduction of drugs and devices.
Adaptive approaches to the introduction of drugs and medical devices involve the use of an evolving evidence base rather than conventional single-point-in-time evaluations as a proposed means to promote patient access to innovation, reduce clinical uncertainty, ensure effectiveness, and improve the health technology development process. This report summarizes a Health Technology Assessment International (HTAi) Policy Forum discussion, drawing on presentations from invited experts, discussions among attendees about real-world case examples, and background paper. For adaptive approaches to be understood, accepted, and implemented, the Forum identified several key issues that must be addressed. These include the need to define the goals of and to set priorities for adaptive approaches; to examine evidence collection approaches; to clarify the roles and responsibilities of stakeholders; to understand the implications of adaptive approaches on current legal and ethical standards; to determine costs of such approaches and how they will be met; and to identify differences in applying adaptive approaches to drugs versus medical devices. The Forum also explored the different implications of adaptive approaches for various stakeholders, including patients, regulators, HTA/coverage bodies, health systems, clinicians, and industry. A key outcome of the meeting was a clearer understanding of the opportunities and challenges adaptive approaches present. Furthermore, the Forum brought to light the critical importance of recognizing and including a full range of stakeholders as contributors to a shared decision-making model implicit in adaptive pathways in future discussions on, and implementation of, adaptive approaches.


Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.
Mild traumatic brain injury (mTBI) resulting from exposure to blast shock waves (BSWs) is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB). Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa) initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction (TJ) proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa) causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy (CTE) and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.


Indirect measures as a signal for evaluative change.
Implicit and explicit attitudes can be changed by using evaluative learning procedures. In this contribution we investigated an asymmetric effect of order of administration of indirect and direct measures on the detection of evaluative change: A change in explicit attitudes is more likely detected if they are measured after implicit attitudes, whereas these latter change regardless of the order. This effect was demonstrated in two studies (n=270; n=138) using the self-referencing task whereas it was not found in a third study (n=151) that used a supraliminal sequential evaluative conditioning paradigm. In all studies evaluative change was present only for contingency aware participants. We discuss a potential explanation underlying the order of measure effect entailing that, in some circumstances, an indirect measure is not only a measure but also a signal that can be detected through self-perception processes and further elaborated at the propositional level.


The deep-sea bacterium Photobacterium profundum SS9 utilizes separate flagellar systems for swimming and swarming under high-pressure conditions.
Motility is a critical function needed for nutrient acquisition, biofilm formation, and the avoidance of harmful chemicals and predators. Flagellar motility is one of the most pressure-sensitive cellular processes in mesophilic bacteria; therefore, it is ecologically relevant to determine how deep-sea microbes have adapted their motility systems for functionality at depth. In this study, the motility of the deep-sea piezophilic bacterium Photobacterium profundum SS9 was investigated and compared with that of the related shallow-water piezosensitive strain Photobacterium profundum 3TCK, as well as that of the well-studied piezosensitive bacterium Escherichia coli. The SS9 genome contains two flagellar gene clusters: a polar flagellum gene cluster (PF) and a putative lateral flagellum gene cluster (LF). In-frame deletions were constructed in the two flagellin genes located within the PF cluster (flaA and flaC), the one flagellin gene located within the LF cluster (flaB), a component of a putative sodium-driven flagellar motor (motA2), and a component of a putative proton-driven flagellar motor (motA1). SS9 PF flaA, flaC, and motA2 mutants were defective in motility under all conditions tested. In contrast, the flaB and motA1 mutants were defective only under conditions of high pressure and high viscosity. flaB and motA1 gene expression was strongly induced by elevated pressure plus increased viscosity. Direct swimming velocity measurements were obtained using a high-pressure microscopic chamber, where increases in pressure resulted in a striking decrease in swimming velocity for E. coli and a gradual reduction for 3TCK which proceeded up to 120 MPa, while SS9 increased swimming velocity at 30 MPa and maintained motility up to a maximum pressure of 150 MPa. Our results indicate that P. profundum SS9 possesses two distinct flagellar systems, both of which have acquired dramatic adaptations for optimal functionality under high-pressure conditions.


Femtosecond laser applications in corneal surgery.
Femtosecond laser (FSL) applications in corneal surgery have increased since its inception. Corneal surgery has undergone a tremendous transformation thanks to the introduction of FSL technology. This laser makes precise, three-dimensional incisions while causing minimal damage to surrounding tissue. This review updates and summarizes current and upcoming FSL applications in corneal surgery, current commercially available FSL, and its respective applications. Refractive surgery applications include laser in-situ keratomileusis flaps, refractive corneal lenticule extraction such as small incision lenticule extraction, astigmatic keratotomy, intracorneal ring segments tunnels for keratoconus including corneal allogenic intrastromal ring segments, and presbyopia treatments with intrastromal pockets for corneal inlays and intrastromal incisions (INTRACOR). Keratoplasty applications include penetrating keratoplasty trephination; superficial and deep anterior lamellar keratoplasty trephination, lamellar dissection, and tunnel creation; posterior lamellar keratoplasty donor and recipient preparation; Bowman layer transplantation donor, and recipient preparation; and stromal keratophakia. Other applications include conjunctival graft preparation in pterygium surgery, and keratopigmentation (corneal tattooing). FSL is a surgical instrument widely used in corneal surgery because it improves reproducibility and safety in many procedures.


Return-to-work interventions integrated into cancer care: a systematic review.
The purpose of this study was to review the literature on the content of interventions focusing on return to work, employment status, or work retention in patients with cancer. Furthermore, the effect of the interventions on return to work was assessed in studies reporting return to work. A literature search was conducted using the databases MEDLINE, PsycINFO, EMBASE and CINAHL. Articles that described a work-directed intervention focusing on return to work, employment status, or work retention in patients with cancer were included. The content of the work-directed part of the interventions was assessed based on two criteria for content analysis: 1. does the setting fit the shared care model of cancer survivor care? 2. Does the intervention target work ability and physical workload? For studies reporting return-to-work outcomes, the return-to-work rates were assessed. For studies that used a control group the ORs and the 95% CIs were calculated. Twenty-three articles describing 19 interventions met the inclusion criteria. Seven studies reported return-to-work outcomes of which four used a control group. Only three interventions aimed primarily at enhancing return to work or employment status. The most frequently reported work-directed components were encouragement, education or advice about work or work-related subjects (68%), vocational or occupational training (21%), or work accommodations (11%). One intervention fit the shared care model of cancer survivor care and five interventions enhanced work ability or decreased physical workload. The rate of return to work ranged from 37% to 89%. In one of the four controlled studies the intervention increased return to work significantly and in the other studies the results were insignificant. Only few interventions are primarily aimed at enhancing return to work in patients with cancer and most do not fit the shared care model involving integrated cancer care. Future studies should be developed with well-structured work-directed components that should be evaluated in randomised controlled trials.


Varicella routine vaccination and the effects on varicella epidemiology - results from the Bavarian Varicella Surveillance Project (BaVariPro), 2006-2011.
In 2004, routine varicella vaccination was recommended in Germany for children 11-14 months of age with one dose, and since 2009, with a second dose at 15-23 months of age. The effects on varicella epidemiology were investigated. Data on varicella vaccinations, cases and complications were collected from annual parent surveys (2006-2011), monthly paediatric practice surveillance (Oct 2006 - Sep 2011; five varicella seasons) and paediatric hospital databases (2005-2009) in the area of Munich (about 238,000 paediatric inhabitants); annual incidences of cases and hospitalisations were estimated. Varicella vaccination coverage (1st dose) in children 18-36 months of age increased in two steps (38%, 51%, 53%, 53%, 66% and 68%); second-dose coverage reached 59% in the 2011 survey. A monthly mean of 82 (62%) practices participated; they applied a total of 50,059 first-dose and 40,541 second-dose varicella vaccinations, with preferential use of combined MMR-varicella vaccine after recommendation of two doses, and reported a total of 16,054 varicella cases <17 years of age. The mean number of cases decreased by 67% in two steps, from 6.6 (95%CI 6.1-7.0) per 1,000 patient contacts in season 2006/07 to 4.2 (95%CI 3.9-4.6) in 2007/08 and 4.0 (95%CI 3.6-4.3) in 2008/09, and further to 2.3 (95%CI 2.0-2.6) in 2009/10 and 2.2 (95%CI 1.9-2.5) in 2010/11. The decrease occurred in all paediatric age groups, indicating herd protection effects. Incidence of varicella was estimated as 78/1,000 children <17 years of age in 2006/07, and 19/1,000 in 2010/11. Vaccinated cases increased from 0.3 (95%0.2-0.3) per 1,000 patient contacts in 2006/07 to 0.4 (95%CI 0.3-0.5) until 2008/09 and decreased to 0.2 (95%CI 0.2-0.3) until 2010/11. The practices treated a total of 134 complicated cases, mainly with skin complications. The paediatric hospitals recorded a total of 178 varicella patients, including 40 (22.5%) with neurological complications and one (0.6%) fatality due to varicella pneumonia. Incidence of hospitalisations decreased from 7.6 per 100,000 children <17 years of age in 2005 to 4.3 in 2009, and from 21.0 to 4.7 in children <5 years of age. Overall, the results show increasing acceptance and a strong impact of the varicella vaccination program, even with still suboptimal vaccination coverage.


The impact of unemployment on mental health examined in a community mental health unit during the recent financial crisis in Greece.
Financial crisis has significant impact on the mental health of the population, resulting in increasing incidence of mental disorders and suicides. Specific social and financial factors mediate the effects of financial crisis on mental health, such as poverty, financial difficulties and unemployment. During the recent international financial crisis, studies in many countries have shown that the worsening of various mental health indicators was related to financial difficulties and unemployment. In Greece, which is one of the countries that experienced intense and prolonged economic and social burden due to the recent crisis, the epidemiological findings were similar and the increase of the prevalence of major depression and suicide was excessive. However, the information about the mental health of the population deriving from health services is limited. The aim of this study was to investigate the impact of the crisis on community mental health -more specifically the rates of mental disorders and suicide, as well as the role of unemployment- among the new cases of a community mental health unit. The sample consisted of 1,865 adult users, men and women, who came seeking for help to the Byron-Kessariani Community Mental Health Centre (CMHC) during the years 2008-2013, i.e. the early years of the current crisis. Regarding the rates of the diagnostic categories in the new cases of CMHC per year, no significant differentiation was observed. There was an increase in the proportion of the unemployed individuals in the total sample of new cases during the study, from 9.65% in 2008 to 26.17% in 2013 and a significant association between unemployment and the occurrence of anxiety and depressive disorders, as indicated by the increase in the proportion of unemployed individuals among new cases with disorders of these categories. There was an upward trend in the rate of new patients referred to CMHC after a suicide attempt, which was doubled during the first years of the crisis. There was also an increase in the rate of unemployed individuals among these cases, from 10% in 2008 to 41.7% in 2009, reaching the highest level in 2011 (53.3%). The findings of this study suggest that during economic crisis unemployment plays an important role in the development of anxiety and depressive disorders and is closely related to suicide attempts. Our results were derived from a specific catchment area and therefore they have high ecological validity.


Biological and symptom changes in posttraumatic stress disorder treatment: a randomized clinical trial.
Understanding cognitive and biological mechanisms of PTSD treatment can help refine treatments and increase rates of response. Thirty-six veterans with PTSD were randomly assigned to receive Prolonged exposure therapy (PE) or Present-Centered therapy (PCT). We examined symptoms, trauma-related cognitions, and two indices of HPA axis function (cortisol awakening response and cortisol response to a script-driven imagery task). Thirty veterans started treatment and 26 completed. PE resulted in significantly more symptom reduction than PCT (P = .008). High treatment responders collapsed across treatments showed nominally higher cortisol levels measured at pretreatment 30 min after trauma script exposure compared to low responders (P = .08). At midtreatment, high treatment responders showed higher cortisol levels throughout the imagery task (Ps = .03-.04). There were no differences between high and low treatment responders at posttreatment. Thoughts of incompetence (F (1.6, 35.8) = 16.8, P = .000) and a dangerous world (F (1.3, 29.9) = 8.2, P = .004) significantly improved over time in high treatment responders but showed no change in low responders. Script-associated cortisol response prior to treatment and reductions in thoughts of incompetence accounted for 83% of the variance in reductions in PTSD severity with PE. Both increased cortisol response to personal trauma script prior to PTSD therapy and reductions in cognitive symptoms of PTSD were significantly and uniquely related to reductions in the core symptoms of PTSD in PE. However, contrary to our hypotheses, cortisol measures were not related to cognitive changes.


Antagonism of some central effects of d-tubocurarine by gamma-aminobutyric acid.
d-Tubocurarine (dtc) administered intracerebroventricularly (icv) to rats produced seizures. Gamma-aminobutyric acid (GABA) administered icv or hydroxylamine administered intraperitoneally (ip) protected the rats from dtc-induced seizures. GABA administered (ip) was ineffective. Local application of dtc to the spinal cord in decerebrate dogs produced facilitation of the scratch reflex. Application of GABA to the spinal cord inhibition the scratch reflex. It is thus concluded that the excitatory effects of dtc on the CNS may be through inhibition of naturally occurring inhibitory substances such as GABA or a closely related compound.


Resolving heterogeneity in depression using individualized structural covariance network analysis.
Elucidating individual aberrance is a critical first step toward precision medicine for heterogeneous disorders such as depression. The neuropathology of depression is related to abnormal inter-regional structural covariance indicating a brain maturational disruption. However, most studies focus on group-level structural covariance aberrance and ignore the interindividual heterogeneity. For that reason, we aimed to identify individualized structural covariance aberrance with the help of individualized differential structural covariance network (IDSCN) analysis. T1-weighted anatomical images of 195 first-episode untreated patients with depression and matched healthy controls (n = 78) were acquired. We obtained IDSCN for each patient and identified subtypes of depression based on shared differential edges. As a result, patients with depression demonstrated tremendous heterogeneity in the distribution of differential structural covariance edges. Despite this heterogeneity, altered edges within subcortical-cerebellum network were often shared by most of the patients. Two robust neuroanatomical subtypes were identified. Specifically, patients in subtype 1 often shared decreased motor network-related edges. Patients in subtype 2 often shared decreased subcortical-cerebellum network-related edges. Functional annotation further revealed that differential edges in subtype 2 were mainly implicated in reward/motivation-related functional terms. In conclusion, we investigated individualized differential structural covariance and identified that decreased edges within subcortical-cerebellum network are often shared by patients with depression. The identified two subtypes provide new insights into taxonomy and facilitate potential clues to precision diagnosis and treatment of depression.


Delayed retrobulbar hematoma after blepharoplasty.
To describe a case of late orbital hematoma after blepharoplasty and review the literature on this subject. A healthy woman developed an orbital hematoma and loss of vision 7 days after an elective blepharoplasty. Computed tomography and magnetic resonance images of the orbits were obtained 1 day after the vascular accident. Computed tomography and magnetic resonance images clearly demonstrated that the site of the hemorrhage was the superior nasal fat pad. Blood from this region molded the globe and accumulated in the intraconal space behind the posterior sclera. The patient was successfully treated with conservative measures only. Orbital hematoma, which is the main cause of loss of vision after blepharoplasty, can be a late postoperative complication.


Elastic network model of allosteric regulation in protein kinase PDK1.
Structural switches upon binding of phosphorylated moieties underpin many signalling networks. The ligand activation is a form of allosteric modulation of the protein, where the binding site is remote from the structural change in the protein. Recently this structural switch has been elegantly demonstrated with the crystallisation of the activated form of 3-phosphoinositide-dependent protein kinase-1 (PDK1). The purpose of the present work is to determine whether the allosteric coupling in PDK1 emerges at the level of a simple coarse grained model of protein dynamics. It is shown here that the allosteric effects of the agonist binding to the small lobe upon the activation loop in the large lobe of PDK1 are explainable within a simple 'ball and spring' elastic network model (ENM) of protein dynamics. In particular, the model shows that the bound phospho peptide mimetic fluctuations have a high degree of correlation with the activation loop of PDK1. The ENM approach to small molecule activation of proteins may offer a first pass predictive methodology where affinity is encoded in residues remote from the active site, and aid in the design of specific protein agonists that enhance the allosteric coupling and antagonist that repress it.


VR cue-exposure treatment for bulimia nervosa.
Several approaches to the treatment of bulimia nervosa have proved effective, including cognitive-behavioral therapy; however, not all patients improve. It is therefore necessary to explore the possibilities of increasing the efficacy of such treatments. One way to attempt this is to incorporate new technologies. This review explores the possibility of developing a new, empirically validated procedure for the treatment of bulimia nervosa patients that involves cue exposure via virtual reality.


Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions.
Cancer-microbe associations have been explored for centuries, but cancer-associated fungi have rarely been examined. Here, we comprehensively characterize the cancer mycobiome within 17,401 patient tissue, blood, and plasma samples across 35 cancer types in four independent cohorts. We report fungal DNA and cells at low abundances across many major human cancers, with differences in community compositions that differ among cancer types, even when accounting for technical background. Fungal histological staining of tissue microarrays supported intratumoral presence and frequent spatial association with cancer cells and macrophages. Comparing intratumoral fungal communities with matched bacteriomes and immunomes revealed co-occurring bi-domain ecologies, often with permissive, rather than competitive, microenvironments and distinct immune responses. Clinically focused assessments suggested prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers, and synergistic predictive performance with bacteriomes.


Treatment of anorexia nervosa in the context of transsexuality: a case report.
Males comprise a minority of patients with eating disorders (ED). However, men who have sex with men, males with gender identity disorder, and transsexual (TS) males are at increased risk for ED. Little has been published about the unique treatment needs of TS patients with ED. A 19-year-old male-to-female TS patient presented with restrictive eating, purging, and weight loss. History revealed that her ED ideation and behaviors were strongly intertwined with her gender identity. She was admitted and during her hospitalization both her ED and TS status were addressed medically. Physicians treating patients with ED should be aware of patients' gender identities and the ways in which gender identity may impact management and recovery. When appropriate, providers should consider addressing medical treatment toward gender transition concurrently with treatment for ED to facilitate medical stabilization and weight restoration in the manner most consistent with the patient's identified gender.


Induction of hepatocyte functional protein expression by submicron/nano-patterning substrates to mimic in vivo structures.
To investigate the influence of bio-inspired metallic superficial topography on the cellular behaviour of a hepatocyte cell line, TiO2 nanopatterns with diversified shapes and heterotropic lateral dimensions were fabricated using electron beam lithography and atomic layer deposition. The dimensional uniformity and shape diversity of the nanopatterns were confirmed using scanning electron microscopy and atomic force microscopy. These topographical nanocues provide good tools for controlling and regulating multiple hepatocellular functions. The expressions of functional proteins such as albumin, transferrin and cytochrome P450 were tested as functional markers. In addition, the change in cellular orientation, cell alignment and native extracellular matrix (ECM) assembly induced by these well-defined nanotopographies were observed. Twelve hours after cell seeding, TiO2 nanogratings with a lateral dimension of 240 nm showed a higher degree of functional protein expression compared to other nanotopographical substrates and a flat surface. These findings suggest that the TiO2 surface resembles a hierarchically-extended collagen nanofibrillar surface and could be recognized by hepatocytes, allowing the proper cytoskeletal orientation and cellular integrity. This TiO2 nanopattern with a specific shape and dimension (240 nm) might therefore emulate ECM biophysical cues, and the intrinsic topography of TiO2 surfaces might evoke enhanced cellular responses. These unique surfaces could be further exploited for tissue engineering and bioreactor technology.


Inducible defenses stay up late: temporal patterns of immune gene expression in Tenebrio molitor.
The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo.


Resonance Raman intensity analysis of ClNO(2) dissolved in methanol.
Halogens such as chlorine are converted from halides, including ClNO(2), to reactive radicals by UV solar radiation. These radicals can affect ozone production and destruction in the stratosphere. Recently, it became clear that halogen radicals can also play a significant role in the chemistry of the troposphere. The photochemistry of ClNO(2) has been the subject of several studies in the gas and solid state that demonstrated a clear phase-dependent reactivity. Here, we report our initial studies of nitryl chloride in solution. Resonance Raman (RR) spectra of ClNO(2) dissolved in methanol after excitation within the 1(1)A(1)-2(1)A(1) absorption band (D band) in the region 200-240 nm are presented. RR intensity along the NO symmetric stretch coordinate (v(1)) at 1291 cm(-1) is observed at all excitation wavelengths, whereas limited intensity corresponding to the transition of the N-Cl symmetric stretch (v(3)) was only observed at 199.8 nm, whereas no intensity corresponding to the O-N-O symmetric bend (v(2)) was observed. Depolarization ratios and absolute resonance Raman cross sections for v(1) were obtained at several excitation wavelengths spanning the D band. Depolarization ratios were found to deviate significantly from 1/3, consistent with more than a single dipole-allowed electronic transition contributing to the scattering. RR intensity analysis (RRIA) reveals that two closely spaced excited electronic states contribute to the scattering, which are dissociative along the Cl-N coordinate. In this study the role the solvent environment plays in ClNO(2) state energetics and excited structural evolution along fundamental coordinates is discussed.


Characterizing Patient-Clinician Communication in Secure Medical Messages: Retrospective Study.
Patient-clinician secure messaging is an important function in patient portals and enables patients and clinicians to communicate on a wide spectrum of issues in a timely manner. With its growing adoption and patient engagement, it is time to comprehensively study the secure messages and user behaviors in order to improve patient-centered care. The aim of this paper was to analyze the secure messages sent by patients and clinicians in a large multispecialty health system at Mayo Clinic, Rochester. We performed message-based, sender-based, and thread-based analyses of more than 5 million secure messages between 2010 and 2017. We summarized the message volumes, patient and clinician population sizes, message counts per patient or clinician, as well as the trends of message volumes and user counts over the years. In addition, we calculated the time distribution of clinician-sent messages to understand their workloads at different times of a day. We also analyzed the time delay in clinician responses to patient messages to assess their communication efficiency and the back-and-forth rounds to estimate the communication complexity. During 2010-2017, the patient portal at Mayo Clinic, Rochester experienced a significant growth in terms of the count of patient users and the total number of secure messages sent by patients and clinicians. Three clinician categories, namely "physician-primary care," "registered nurse-specialty," and "physician-specialty," bore the majority of message volume increase. The patient portal also demonstrated growing trends in message counts per patient and clinician. The "nurse practitioner or physician assistant-primary care" and "physician-primary care" categories had the heaviest per-clinician workload each year. Most messages by the clinicians were sent from 7 AM to 5 PM during a day. Yet, between 5 PM and 7 PM, the physicians sent 7.0% (95,785/1,377,006) of their daily messages, and the nurse practitioner or physician assistant sent 5.4% (22,121/408,526) of their daily messages. The clinicians replied to 72.2% (1,272,069/1,761,739) patient messages within 1 day and 90.6% (1,595,702/1,761,739) within 3 days. In 95.1% (1,499,316/1,576,205) of the message threads, the patients communicated with their clinicians back and forth for no more than 4 rounds. Our study found steady increases in patient adoption of the secure messaging system and the average workload per clinician over 8 years. However, most clinicians responded timely to meet the patients' needs. Our study also revealed differential patient-clinician communication patterns across different practice roles and care settings. These findings suggest opportunities for care teams to optimize messaging tasks and to balance the workload for optimal efficiency.


Do Decision Aids Benefit Patients with Chronic Musculoskeletal Pain? A Systematic Review.
To review the effect of patient decision aids for adults making treatment decisions regarding the management of chronic musculoskeletal pain. We performed a systematic review of randomized controlled trials of adults using patient decision aids to make treatment decisions for chronic musculoskeletal pain in the outpatient setting. Of 477 records screened, 17 met the inclusion criteria. Chronic musculoskeletal pain conditions included osteoarthritis of the hip, knee, or trapeziometacarpal joint and back pain. Thirteen studies evaluated the use of a decision aid for deciding between surgical and nonsurgical management. The remaining four studies evaluated decision aids for nonsurgical treatment options. Outcomes included decision quality, pain, function, and surgery utilization. The effects of decision aids on decision-making outcomes were mixed. Comparing decision aids with usual care, all five studies that examined knowledge scores found improvement in patient knowledge. None of the four studies that evaluated satisfaction with the decision-making process found a difference with use of a decision aid. There was limited and inconsistent data on other decision-related outcomes. Of the eight studies that evaluated surgery utilization, seven found no difference in surgery rates with use of a decision aid. Five studies made comparisons between different types of decision aids, and there was no clearly superior format. Decision aids may improve patients' knowledge about treatment options for chronic musculoskeletal pain but largely did not impact other outcomes. Future efforts should focus on improving the effectiveness of decision aids and incorporating nonpharmacologic and nonsurgical management options.


Implementation and Evaluation of Guillain-Barré Syndrome Surveillance in Puerto Rico during the 2016 Zika Virus Epidemic.
Guillain-Barré syndrome (GBS) is an uncommon autoimmune disorder that follows infection or vaccination, and increased incidence has been reported during Zika virus (ZIKV) transmission. During the 2016 ZIKV epidemic, the Puerto Rico Department of Health (PRDH) implemented the Enhanced GBS Surveillance System (EGBSSS). Here, we describe EGBSSS implementation and evaluate completeness, validity, and timeliness. GBS cases were identified using passive surveillance and discharge diagnostic code for GBS. Completeness was evaluated by capture-recapture methods. Sensitivity and positive predictive value (PPV) for confirmed GBS cases were calculated for both case identification methods. Median time to completion of key time steps were compared by quarter (Q1-4) and hospital size. A total of 122 confirmed GBS cases with onset of neurologic illness in 2016 were identified. Capture-recapture methodology estimated that four confirmed GBS cases were missed by both identification methods. Identification of cases by diagnostic code had a higher sensitivity than passive surveillance (89% vs. 80%), but a lower PPV (60% vs. 72%). There was a significant decrease from Q1 to Q3 in median time from hospital admission to case reporting (11 days vs. 2 days, p = 0.032) and from Q2 to Q3 in median time from specimen receipt to arbovirus laboratory test reporting (35 days vs. 26 days, p = 0.004). EGBSSS provided complete, valid, and increasingly timely surveillance data, which guided public health action and supported healthcare providers during the ZIKV epidemic. This evaluation provides programmatic lessons for GBS surveillance and emergency response surveillance.


Optimization of the splice loss between photonic-bandgap fibers and conventional single-mode fibers.
To understand the loss limitations of a splice between a hollow-core fiber and a conventional fiber, we use a numerical model to calculate the expected coupling loss between the NKT Photonics' HC-1550-02 fiber and a single-mode fiber (SMF) of arbitrary step-index profile. When the SMF parameters are optimized, the splice loss is predicted to be as low as approximately 0.6 dB. This minimum is believed to be largely due to mode-shape mismatch. These predictions are confirmed experimentally by optimizing the splice loss between this photonic-bandgap fiber and five SMFs with different mode-field diameters (MFDs) and V numbers. With the SMF-28 fiber, the measured loss is 1.3 dB, in excellent agreement with theory. Using a SMF with parameters close to the optimum values (MFD=7.2 microm and V=2.16), this loss was reduced to a new record value of 0.79 dB.


In-vivo sensitivity of Plasmodium vivax isolates from Rond nia (western Amazon region, Brazil) to regimens including chloroquine and primaquine.
Seventy-nine adults with Plasmodium vivax malaria, from the Porto Velho area of Rond nia (western Amazon region, Brazil), gave informed consent to participate in a blind, clinical study of two regimens of treatment with chloroquine (CQ) and primaquine. The effectiveness of the 'classical' regimen (CQ for 3 days, followed by primaquine for 14 days) was compared with that of a 'short' regimen in which the two drugs were given simultaneously for 5 days. There were no cases of recrudescence indicative of CQ resistance (i.e. within 30 days of the first treatment dose) among the 73 patients who each completed a full, supervised course of treatment. However, 10 cases of apparent relapse were observed (all > 60 days after first treatment dose), representing 6.5% (2/31) of the patients who completed 60 days of follow-up after the classical treatment and 26.7% (8/30) of the short-regimen patients who completed the same period of follow-up. PCR-based comparison of parasitic DNA collected pre- and post-treatment was successful for eight of the 10 cases of apparent relapse and indicated that two such cases, both given the short regimen of treatment, were, in fact, probable cases of re-infection rather than of relapse. The results indicate that the classical schedule of treatment with chloroquine and primaquine was more effective at preventing relapses than the short regimen. However, since prolonged treatment with primaquine often produces side-effects that are severe enough to reduce compliance, the short schedule could be a useful alternative for malaria control in endemic areas of the Amazon region.


The reconstructed cranium of Pierolapithecus and the evolution of the great ape face.
Pierolapithecus catalaunicus (~12 million years ago, northeastern Spain) is key to understanding the mosaic nature of hominid (great ape and human) evolution. Notably, its skeleton indicates that an orthograde (upright) body plan preceded suspensory adaptations in hominid evolution. However, there is ongoing debate about this species, partly because the sole known cranium, preserving a nearly complete face, suffers from taphonomic damage. We 1) carried out a micro computerized tomography (CT) based virtual reconstruction of the Pierolapithecus cranium, 2) assessed its morphological affinities using a series of two-dimensional (2D) and three-dimensional (3D) morphometric analyses, and 3) modeled the evolution of key aspects of ape face form. The reconstruction clarifies many aspects of the facial morphology of Pierolapithecus. Our results indicate that it is most similar to great apes (fossil and extant) in overall face shape and size and is morphologically distinct from other Middle Miocene apes. Crown great apes can be distinguished from other taxa in several facial metrics (e.g., low midfacial prognathism, relatively tall faces) and only some of these features are found in Pierolapithecus, which is most consistent with a stem (basal) hominid position. The inferred morphology at all ancestral nodes within the hominoid (ape and human) tree is closer to great apes than to hylobatids (gibbons and siamangs), which are convergent with other smaller anthropoids. Our analyses support a hominid ancestor that was distinct from all extant and fossil hominids in overall facial shape and shared many features with Pierolapithecus. This reconstructed ancestral morphotype represents a testable hypothesis that can be reevaluated as new fossils are discovered.


Differential ontogeny of opioid, dopaminergic and serotonergic regulation of prolactin secretion.
The goal of this study was to determine if the opioid system which is stimulatory to prolactin (PRL) secretion develops before the serotonergic system which regulates PRL release. The opioid and serotonergic systems were chosen for comparison because evidence exists that functional serotonergic neurons are necessary for opiate-induced PRL secretion in adult rats. Haloperidol and morphine produced a dose-related stimulation of PRL release in animals of all ages. In contrast, the serotonin agonists, quipazine and m-chlorophenylpiperazine, and the serotonin-releasing drug p-chloroamphetamine produced dose-related increases in PRL release in adult rats, but not in neonatal rats. The PRL response to the serotonin precursor 5-hydroxytryptophan was potentiated by fluoxetine only in animals 15 days of age or older. PRL secretion induced by these serotonergic agents was blocked by cyproheptadine, a serotonin receptor antagonist. Unlike PRL, corticosterone and growth hormone secretion were stimulated by quipazine and 5-hydroxytryptophan plus fluoxetine in both adult and neonatal rats. These findings suggest that stimulatory opioid control of PRL secretion and the dopaminergic mechanism which tonically inhibits PRL release are intact in the neonatal rat. In contrast, the stimulatory serotonergic mechanism is not functional until between 10 to 15 days of age. This late maturation appears to be specific to the serotonergic neurons regulating PRL release because the corticosterone and growth hormone responses to serotonergic stimulation develop early in ontogeny.


Retrieval of embolized tip of port catheter from branch of right pulmonary artery using a macro snare catheter.
Rupture of the silicon port catheter is a relatively rare complication. Ruptured part usually embolizes; therefore, removal of foreign body may be difficult. These ports usually migrate to right-sided chambers, main pulmonary arteries, and pulmonary subbranches. Different devices such as snares, basket catheters, and ablation catheters are utilized for retrieval. Hereby, we report successful extraction of an embolized 10-cm tip of a vascular access port using a macro snare catheter.


Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex.
Realizing the full utility of brain organoids to study human development requires understanding whether organoids precisely replicate endogenous cellular and molecular events, particularly since acquisition of cell identity in organoids can be impaired by abnormal metabolic states. We present a comprehensive single-cell transcriptomic, epigenetic, and spatial atlas of human cortical organoid development, comprising over 610,000 cells, from generation of neural progenitors through production of differentiated neuronal and glial subtypes. We show that processes of cellular diversification correlate closely to endogenous ones, irrespective of metabolic state, empowering the use of this atlas to study human fate specification. We define longitudinal molecular trajectories of cortical cell types during organoid development, identify genes with predicted human-specific roles in lineage establishment, and uncover early transcriptional diversity of human callosal neurons. The findings validate this comprehensive atlas of human corticogenesis in vitro as a resource to prime investigation into the mechanisms of human cortical development.


A new neurologic and adaptive capacity scoring system for evaluating obstetric medications in full-term newborns.
A variety of examinations are currently available for evaluating the neurobehavior of the newborn. These exams are often difficult and time-consuming to perform, require extensive training of the examiners, and produce results that may be difficult to interpret. The authors describe a new Neurologic and Adaptive Capacity Score (NACS) for full-term neonates and compare it with the Scanlon Early Neonatal Neurobehavioral Scale (ENNS), the most widely used test for evaluating effects of obstetric medication on the neonate. The NACS was designed as a screening test to detect central nervous system depression from drugs and also to differentiate these effects from those found after birth trauma and perinatal asphyxia. The NACS is based on 20 criteria, each of which is given a score of 0, 1, or 2. These criteria assess five general areas: 1) adaptive capacity; 2) passive tone; 3) active tone; 4) primary reflexes; and 5) alertness, crying, and motor activity (general observations). In contrast to the ENNS, the NACS places more emphasis on motor tone, avoids the use of noxious stimuli (pinprick, repeated Moro examinations), takes half the time to perform, and provides for any given baby a single number that immediately identifies a depressed or vigorous neonate.


Localization of ion-regulatory epithelia in embryos and hatchlings of two cephalopods.
The tissue distribution and ontogeny of Na(+)/K(+)-ATPase has been examined as an indicator for ion-regulatory epithelia in whole animal sections of embryos and hatchlings of two cephalopod species: the squid Loligo vulgaris and the cuttlefish Sepia officinalis. This is the first report of the immunohistochemical localization of cephalopod Na(+)/K(+)-ATPase with the polyclonal antibody alpha (H-300) raised against the human alpha1-subunit of Na(+)/K(+)-ATPase. Na(+)/K(+)-ATPase immunoreactivity was observed in several tissues (gills, pancreatic appendages, nerves), exclusively located in baso-lateral membranes lining blood sinuses. Furthermore, large single cells in the gill of adult L. vulgaris specimens closely resembled Na(+)/K(+)-ATPase-rich cells described in fish. Immunohistochemical observations indicated that the amount and distribution of Na(+)/K(+)-ATPase in late cuttlefish embryos was similar to that found in juvenile and adult stages. The ion-regulatory epithelia (e.g., gills, excretory organs) of the squid embryos and paralarvae exhibited less differentiation than adults. Na(+)/K(+)-ATPase activities for whole animals were higher in hatchlings of S. officinalis (157.0 +/- 32.4 micromol g (FM) (-1) h(-1)) than in those of L. vulgaris (31.8 +/- 3.3 micromol g (FM) (-1) h(-1)). S. officinalis gills and pancreatic appendages achieved activities of 94.8 +/- 18.5 and 421.8 +/- 102.3 micromol(ATP) g (FM) (-1) h(-1), respectively. High concentrations of Na(+)/K(+)-ATPase in late cephalopod embryos might be important in coping with the challenging abiotic conditions (low pH, high pCO(2)) that these organisms encounter inside their eggs. Our results also suggest a higher sensitivity of squid vs. cuttlefish embryos to environmental acid-base disturbances.


Fetal alcohol spectrum disorder among pre-adopted and foster children.
Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disorders. Children in foster care or domestically adopted are at greater risk for FASD. The aim of this study was to determine the prevalence or risk for FASD in a selected population of foster and adopted children. Children between 2 and 12 years who were candidates for adoption in foster care were evaluated for clinical manifestations and historical features of fetal alcohol spectrum disorder based on established criteria for FASD. Of the 89 children evaluated, 18 had mothers with a confirmed history of alcohol consumption during pregnancy. Two children had fetal alcohol syndrome and one had partial fetal alcohol syndrome. In addition, five had alcohol-related neurodevelopmental disorder, one had alcohol-related birth defects, and a single child had manifestations of both. Of the 71 children in which fetal alcohol exposure could not be confirmed, many had manifestations that would have established a diagnosis of FASD were a history of maternal alcohol consumption obtained. In a population of high-risk children seen in an adoption clinic, many had manifestations associated with FASD especially where prenatal alcohol exposure was established. The reported prevalence in this study is higher than that reported in our previous study of younger children. This is most likely due to the higher number of children diagnosed with alcohol-related neurodevelopmental disorders that typically manifest at an older age.


Metagenomic comparison of the rectal microbiota between rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis).
Rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are frequently used in establishing animal models for human diseases. To determine the differences in gut microbiota between these species, rectal swabs from 20 rhesus macaques and 21 cynomolgus macaques were collected, and the microbial composition was examined by deep sequencing of the 16S rRNA gene. We found that the rectal microbiota of cynomolgus macaques exhibited significantly higher alpha diversity than that of rhesus macaques, although the observed number of operational taxonomic units (OTUs) was almost the same. The dominant taxa at both the phylum and genus levels were similar between the two species, although the relative abundances of these dominant taxa were significantly different between them. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed significant differences in the functional components between the microbiota of the two species, in particular the lipopolysaccharide (LPS) synthesis proteins. The above data indicated significant differences in microbial composition and function between these two closely related macaque species, which should be taken into consideration in the future selection of these animals for disease models.


Tinnitus: current understanding and contemporary management.
Tinnitus is a debilitating condition that affects a broad range of patients. Despite thorough and extensive research, the cause of tinnitus has yet to be determined. Also, there has never been a single intervention identified that can consistently eliminate the symptoms of tinnitus. However, despite our inability to 'cure' tinnitus, there are many medical and behavioral strategies that may result in symptomatic relief. The purpose of this article is to review some of the previous information on tinnitus and to examine the recent research on the etiology and management of this condition. Recent research into the etiology of tinnitus has demonstrated that genetics plays less of a role than previously thought. Although many medications can cause some relief of tinnitus, a number of well designed studies have failed to identify a single cure. For patients with severe tinnitus who have failed other treatments, such as dietary modification, herbs and nutrients, sound therapies (tinnitus retraining, Neuromonics, masking, and others), or centrally acting medications, transcranial magnetic stimulation has emerged as a viable treatment option. Tinnitus is a common medical complaint and debilitating problem for some patients. It has a broad range of etiologies and even more potential treatments. This review is meant to inform the reader on the current options available to treat this condition.


Gabion water barrier structures as a sustainable approach to water and land conservation.
Gabions involve low construction technology and are flexible, economically viable, and environmentally friendly. They are now widely accepted as a standard construction material on a global scale. Gabion water barrier structures can be used for a variety of objectives, including flood control, land development, regulation of sediment transport, and catchment restoration. While intense water runoff can cause a large hole or submerge regions in solid water barrier constructions, gabion structures can sink down into the earth and protect the land from environmental and economic damage. The present study reviews the design/construction procedure of gabion water barrier structures and field/laboratory and numerical investigations for their performance in water and land conservation. Various applications of gabion water barrier structures, especially for economic/social impact and environmental degradation control, which qualify the gabion water barrier structures as a sustainable technique for water and land conservation, are reviewed. Future aspects and challenges ahead are also discussed.


Principles of antimicrobial therapy.
We have discussed important factors involved in choosing appropriate antimicrobial regimens for the treatment of bacterial meningitis and brain abscess to illustrate common themes relevant to the treatment of these diseases. We have limited this review to these conditions for two main reasons: (1) the principles involved in optimal antimicrobial therapy for these diseases likely apply to others CNS infections, such as viral and fungal diseases; and (2) little pharmacological information is currently available for other types of CNS infections. Many of the studies addressing the relevant pharmacological and microbiological aspects of antimicrobial therapy for CNS infections have been performed in experimental animal models and, as a result, the information derived from these studies may be different when examined in appropriate human studies. Our current understanding of appropriate antimicrobial therapy for CNS infections may be summarized as follows: 1. Choose bactericidal antimicrobials that effectively cross the BBB to achieve CSF concentrations well above the MBC (≥ 10-fold) for the suspected bacterial pathogen(s). 2. Take into consideration the relevant PD parameters the bactericidal activity of the antimicrobials used to treat bacterial meningitis, such as t > MBC or AUC/MBC. 3. Tailor the antimicrobial regimen based on microbiological information, once available. However, with respect to brain abscess therapy, keep in mind that anaerobes are commonly involved, but difficult to culture, and consider including antianaerobic therapy even if the bacterial cultures do not grow anaerobes. 4. Treat bacterial meningitis caused by nonmeningococcal pathogens for 7-10 days, but monitor clinical progress to determine whether the patient should continue on a more prolonged antimicrobial course. Meningococcal meningitis may be treated with 3-4 days of effective antimicrobial therapy, again with the caveat that the patients clinical course should dictate duration of therapy. 5. Treat brain abscess, preferably after aspiration/drainage, for at least 6 weeks with intravenous antimicrobials for brain abscess on the clinical response (e.g., improved symptoms, lack of new neurological findings) and radiographic changes (e.g., reduction in cavity size).


Heterogeneity of the humoral immune response following Staphylococcus aureus bacteremia.
Expanding knowledge on the humoral immune response in Staphylococcus aureus-infected patients is a mandatory step in the development of vaccines and immunotherapies. Here, we present novel insights into the antibody responses following S. aureus bacteremia. Fifteen bacteremic patients were followed extensively from diagnosis onwards (median 29 days, range 9-74). S. aureus strains (median 3, range 1-6) and serial serum samples (median 16, range 6-27) were collected. Strains were genotyped by pulsed-field gel electrophoresis (PFGE) and genes encoding 19 staphylococcal proteins were detected by polymerase chain reaction (PCR). The levels of IgG, IgA, and IgM directed to these proteins were determined using bead-based flow cytometry. All strains isolated from individual patients were PFGE-identical. The genes encoding clumping factor (Clf) A, ClfB, and iron-responsive surface-determinant (Isd) A were detected in all isolates. Antigen-specific IgG levels increased more frequently than IgA or IgM levels. In individual patients, different proteins induced an immune response and the dynamics clearly differed. Anti-ClfB, anti-IsdH, and anti-fibronectin-binding protein A IgG levels increased in 7 of 13 adult patients (p < 0.05). The anti-IsdA IgG level increased in 12 patients (initial to peak level: 1.13-10.72 fold; p < 0.01). Peak level was reached 7-37 days after diagnosis. In a bacteremic 5-day-old newborn, antistaphylococcal IgG levels declined from diagnosis onwards. In conclusion, each bacteremic patient develops a unique immune response directed to different staphylococcal proteins. Therefore, vaccines should be based on multiple components. IsdA is immunogenic and, therefore, produced in nearly all bacteremic patients. This suggests that IsdA might be a useful component of a multivalent staphylococcal vaccine.


Time delays in each step from symptom onset to treatment in acute myocardial infarction: Results from a nation-wide TURKMI registry.
In this study, we aimed to analyze the TURKMI registry to identify the factors associated with delays from symptom onset to treatment that would be the focus of improvement efforts in patients with acute myocardial infarction (AMI) in Turkey. The TURKMI study is a nation-wide registry that was conducted in 50 centers capable of 24/7 primary percutaneous coronary intervention (PCI). All consecutive patients (n=1930) with AMI admitted to coronary care units within 48 hours of symptom onset were prospectively enrolled during a predefined 2-week period between November 1, 2018, and November 16, 2018. All the patients were examined in detail with regard to the time elapsed at each step from symptom onset to initiation of treatment, including door-to-balloon time (D2B) and total ischemic time (TIT). After excluding patients who suffered an AMI within the hospital (2.6%), the analysis was conducted for 1879 patients. Most of the patients (49.5%) arrived by self-transport, 11.8% by emergency medical service (EMS) ambulance, and 38.6% were transferred from another EMS without PCI capability. The median time delay from symptom-onset to EMS call was 52.5 (15-180) min and from EMS call to EMS arrival 15 (10-20) min. In ST-segment elevation myocardial infarction (STEMI), the median D2B time was 36.5 (25-63) min, and median TIT was 195 (115-330) min. TIT was significantly prolonged from 151 (90-285) min to 250 (165-372) min in patients transferred from non-PCI centers. The major significant factors associated with time delay were patient-related delay and the mode of hospital arrival, both in STEMI and non-STEMI. The baseline evaluation of the TURKMI study revealed that an important proportion of patients presenting with AMI within 48 hours of symptom onset reach the PCI treatment center later than the time proposed in the guidelines, and the use of EMS for admission to hospital is extremely low in Turkey. Patient-related factors and the mode of hospital admission were the major factors associated with the time delay to treatment.


Targeted LC-MS/MS profiling of bile acids reveals primary/secondary bile acid ratio as a novel biomarker for necrotizing enterocolitis.
Bile acids (BAs) are involved in the development of necrotizing enterocolitis (NEC), which mainly occurs in preterm infants. We aim to identify the change of BAs in preterm infants and validate its potential value in the detection of NEC. Targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to measure the plasma BAs in healthy preterm infants and patients with NEC. By analyzing the level of BAs in healthy preterm infants, we found that the plasma concentrations of BAs were related to sex, gestational/postnatal age, birth weight, mode of birth, and feeding type after birth. The plasma levels of TCA, GCA, TCDCA, GCDCA, primary BAs, and total BAs and the primary/secondary BA ratio were decreased, while DCA, UDCA, and secondary BAs were increased in NEC. The primary/secondary BA ratio (cutoff point 62.9) can effectively differentiate NEC from healthy preterm infants, with an AUC of 0.9, a sensitivity of 94.5%, and a specificity of 78.1%. Combining the ratio with high-risk factors of NEC can better distinguish between NEC and control, with an AUC of 0.95. Importantly, significantly lower levels of primary/secondary BA ratio were found in infants with surgical NEC than in nonsurgical NEC cases. The cutoff point of 28.7 identified surgical NEC from nonsurgical NEC with sensitivity and specificity of 76.9% and 100%. Thus, our study identified that the primary/secondary BA ratio in the plasma can differentiate NEC from healthy preterm infants and effectively differentiate the surgical NEC from nonsurgical NEC. Therefore, LC-MS/MS was expected to be a novel measurement platform used to distinguish infants who are most in need of close monitoring or early surgical intervention.


Observing vessel stumps axially: A novel exoscope for end-to-end microvascular anastomosis.
Although many free tissue transfers have been performed, free flap loss can still occur because of vascular compromise. To facilitate microsurgery, we invented the axial-view microscope (aMS), a new type of microscope that can axially visualize vessel stumps. The aMS was combined with an optical microscope, the so-called bird's-eye-view microscope (bMS). Using our aMS, we observed the cross-sections of the following 12 arteries during vascular anastomosis: three deep inferior epigastric arteries, three suprathyroid arteries, two thoracodorsal arteries, two jejunal arteries, one lateral circumflex femoral artery, and one facial artery. For each artery, we measured the vessel height-to-width (H-W) ratio to determine the roundness of the vessel stump. Based on the aMS and bMS, the average H-W ratios were 0.877 ± 0.187 and 0.445 ± 0.172, respectively. The H-W ratio obtained using the aMS was significantly higher than that of the bMS (P < 0.001). Providing the surgeon with a bidirectional view of the vessel stump reduced blind spots at the anastomotic site. In this report, we describe our new microscope and associated clinical cases.


Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age.
Vitamin and mineral deficiencies, particularly those of iron, vitamin A, and zinc, affect more than two billion people worldwide. Young children are highly vulnerable because of rapid growth and inadequate dietary practices. Multiple micronutrient powders (MNPs) are single-dose packets containing multiple vitamins and minerals in powder form, which are mixed into any semi-solid food for children six months of age or older. The use of MNPs for home or point-of-use fortification of complementary foods has been proposed as an intervention for improving micronutrient intake in children under two years of age. In 2014, MNP interventions were implemented in 43 countries and reached over three million children. This review updates a previous Cochrane Review, which has become out-of-date. To assess the effects and safety of home (point-of-use) fortification of foods with MNPs on nutrition, health, and developmental outcomes in children under two years of age. For the purposes of this review, home fortification with MNP refers to the addition of powders containing vitamins and minerals to semi-solid foods immediately before consumption. This can be done at home or at any other place that meals are consumed (e.g. schools, refugee camps). For this reason, MNPs are also referred to as point-of-use fortification. We searched the following databases up to July 2019: CENTRAL, MEDLINE, Embase, and eight other databases. We also searched four trials registers, contacted relevant organisations and authors of included studies to identify any ongoing or unpublished studies, and searched the reference lists of included studies. We included randomised controlled trials (RCTs) and quasi-RCTs with individual randomisation or cluster-randomisation. Participants were infants and young children aged 6 to 23 months at the time of intervention, with no identified specific health problems. The intervention consisted of consumption of food fortified at the point of use with MNP formulated with at least iron, zinc, and vitamin A, compared with placebo, no intervention, or use of iron-containing supplements, which is standard practice. Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, and assessed the risk of bias of included studies. We reported categorical outcomes as risk ratios (RRs) or odds ratios (ORs), with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) and 95% CIs. We used the GRADE approach to assess the certainty of evidence. We included 29 studies (33,147 children) conducted in low- and middle-income countries in Asia, Africa, Latin America, and the Caribbean, where anaemia is a public health problem. Twenty-six studies with 27,051 children contributed data. The interventions lasted between 2 and 44 months, and the powder formulations contained between 5 and 22 nutrients. Among the 26 studies contributing data, 24 studies (26,486 children) compared the use of MNP versus no intervention or placebo; the two remaining studies compared the use of MNP versus an iron-only supplement (iron drops) given daily. The main outcomes of interest were related to anaemia and iron status. We assessed most of the included studies at low risk of selection and attrition bias. We considered some studies to be at high risk of performance and detection bias due to lack of blinding. Most studies were funded by government programmes or foundations; only two were funded by industry. Home fortification with MNP, compared with no intervention or placebo, reduced the risk of anaemia in infants and young children by 18% (RR 0.82, 95% CI 0.76 to 0.90; 16 studies; 9927 children; moderate-certainty evidence) and iron deficiency by 53% (RR 0.47, 95% CI 0.39 to 0.56; 7 studies; 1634 children; high-certainty evidence). Children receiving MNP had higher haemoglobin concentrations (MD 2.74 g/L, 95% CI 1.95 to 3.53; 20 studies; 10,509 children; low-certainty evidence) and higher iron status (MD 12.93 μg/L, 95% CI 7.41 to 18.45; 7 studies; 2612 children; moderate-certainty evidence) at follow-up compared with children receiving the control intervention. We did not find an effect on weight-for-age (MD 0.02, 95% CI -0.03 to 0.07; 10 studies; 9287 children; moderate-certainty evidence). Few studies reported morbidity outcomes (three to five studies each outcome) and definitions varied, but MNP did not increase diarrhoea, upper respiratory infection, malaria, or all-cause morbidity. In comparison with daily iron supplementation, the use of MNP produced similar results for anaemia (RR 0.89, 95% CI 0.58 to 1.39; 1 study; 145 children; low-certainty evidence) and haemoglobin concentrations (MD -2.81 g/L, 95% CI -10.84 to 5.22; 2 studies; 278 children; very low-certainty evidence) but less diarrhoea (RR 0.52, 95% CI 0.38 to 0.72; 1 study; 262 children; low-certainty of evidence). However, given the limited quantity of data, these results should be interpreted cautiously. Reporting of death was infrequent, although no trials reported deaths attributable to the intervention. Information on side effects and morbidity, including malaria and diarrhoea, was scarce. It appears that use of MNP is efficacious among infants and young children aged 6 to 23 months who are living in settings with different prevalences of anaemia and malaria endemicity, regardless of intervention duration. MNP intake adherence was variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups. Home fortification of foods with MNP is an effective intervention for reducing anaemia and iron deficiency in children younger than two years of age. Providing MNP is better than providing no intervention or placebo and may be comparable to using daily iron supplementation. The benefits of this intervention as a child survival strategy or for developmental outcomes are unclear. Further investigation of morbidity outcomes, including malaria and diarrhoea, is needed. MNP intake adherence was variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups.


Social function of adult men with attention-deficit/hyperactivity disorder in the context of military service.
This study examined the characteristics of adult men with attention-deficit/hyperactivity disorder (ADHD) on social outcomes with particular focus on social function in the context of military service. Eighty-nine adult male outpatients diagnosed with ADHD in adulthood were included in this retrospective chart review study. Participants were divided into two groups: "military service group (MS)" (those who had completed military duty) and "nonmilitary service group (NMS)" (those who were exempted from conscription or engaged in public service). MS included 50 subjects and NMS included 39 subjects. The age at first ADHD diagnosis, intelligence quotient (IQ), occupation, and psychiatric comorbidities were compared between the two groups. The age at first diagnosis, IQ, and number of employed participants were significantly higher in MS than in NMS. NMS had significantly more psychiatric comorbidities than those in MS. In both groups, depression was the most common psychiatric comorbidity. Logistic regression analysis showed that the subjects' IQ, psychiatric comorbidity, and age at first diagnosis were determinants of military duty completion. The results strongly suggested that IQ and psychiatric comorbidities are the most crucial factors affecting military service in male adults with ADHD, independent of ADHD.


Impact of congenital diaphragmatic hernia on diaphragm muscle function in neonatal rats.
Congenital diaphragmatic hernia (CDH) is characterized by incomplete partitioning of the thoracic and abdominal cavities by the diaphragm muscle (DIAm). The resulting in utero invasion of the abdominal viscera into the thoracic cavity leads to impaired fetal breathing movements, severe pulmonary hypoplasia, and pulmonary hypertension. We hypothesized that in a well-established rodent model of Nitrofen-induced CDH, DIAm isometric force generation, and DIAm fiber cross-sectional areas would be reduced compared with nonlesioned littermate and Control pups. In CDH and nonlesioned pups at embryonic day 21 or birth, DIAm isometric force responses to supramaximal field stimulation (200 mA, 0.5 ms duration pulses in 1-s duration trains at rates ranging from 10 to 100 Hz) was measured ex vivo. Further, DIAm fatigue was determined in response to 120 s of repetitive stimulation at 40 Hz in 330-ms duration trains repeated each second. The DIAm was then stretched to Lo, frozen, and fiber cross-sectional areas were measured in 10 μm transverse sections. In CDH pups, there was a marked reduction in DIAm-specific force and force following 120 s of fatiguing contraction. The cross-sectional area of DIAm fibers was also reduced in CDH pups compared with nonlesioned littermates and Control pups. These results show that CDH is associated with a dramatic weakening of the DIAm, which may contribute to poor survival despite various surgical efforts to repair the hernia and improve lung development.NEW & NOTEWORTHY There are notable respiratory deficits related to congenital diaphragmatic hernia (CDH), yet the contribution, if any, of frank diaphragm muscle weakness to CDH is unexplored. Here, we use the well-established Nitrofen teratogen model to induce CDH in rat pups, followed by diaphragm muscle contractility and morphological assessments. Our results show diaphragm muscle weakness in conjunction with reduced muscle fiber density and size, contributing to CDH morbidity.


Linkage of Gitelman syndrome to the thiazide-sensitive sodium-chloride cotransporter gene with identification of mutations in Dutch families.
Gitelman syndrome is a mostly autosomal recessive disorder affecting the renal tubular function associated with hypokalemia and hypomagnesemia. Functional studies point to a defect in the distal renal tubule in the thiazide-sensitive, electroneutral sodium-chloride co-transporter (TSC). Based upon the localization of a 2.6 cDNA encoding the human TSC to chromosome 16q13, polymorphic markers spanning the region from 16p12 to 16q21 were tested for linkage to the Gitelman syndrome locus in three Dutch families with autosomal recessive inheritance of this disorder. Using two-point linkage analysis, a maximum LOD score (Zmax of 4.49 (at theta = 0.00) was found for the marker D16S408. One crucial recombination event places the Gitelman syndrome locus distal to D16S419 at 16q12-13. Subsequently we have tested our group of Gitelman patients for mutations in the human TSC gene. Two mutations were identified in three Gitelman families. Our study confirms that the human TSC gene is involved in Gitelman syndrome. Patients from three Gitelman families reveal two identical human TSC mutations, suggesting these families share a common ancestor.


Diatom Microbubbler for Active Biofilm Removal in Confined Spaces.
Bacterial biofilms form on and within many living tissues, medical devices, and engineered materials, threatening human health and sustainability. Removing biofilms remains a grand challenge despite tremendous efforts made so far, particularly when they are formed in confined spaces. One primary cause is the limited transport of antibacterial agents into extracellular polymeric substances (EPS) of the biofilm. In this study, we hypothesized that a microparticle engineered to be self-locomotive with microbubbles would clean a structure fouled by biofilm by fracturing the EPS and subsequently improving transports of the antiseptic reagent. We examined this hypothesis by doping a hollow cylinder-shaped diatom biosilica with manganese oxide (MnO2) nanosheets. In an antiseptic H2O2 solution, the diatoms doped by MnO2 nanosheets, denoted as diatom bubbler, discharged oxygen gas bubbles continuously and became self-motile. Subsequently, the diatoms infiltrated the bacterial biofilm formed on either flat or microgrooved silicon substrates and continued to generate microbubbles. The resulting microbubbles merged and converted surface energy to mechanical energy high enough to fracture the matrix of biofilm. Consequently, H2O2 molecules diffused into the biofilm and killed most bacterial cells. Overall, this study provides a unique and powerful tool that can significantly impact current efforts to clean a wide array of biofouled products and devices.