Initial clinical efficacy of 3-mm implants immediately placed into function in conditions of limited spacing.
The objective of this study was to determine changes in interdental papillae, alveolar bone loss, esthetics, and initial healing survival when 1-piece narrow-diameter implants were immediately loaded in sites with limited tooth-to-tooth spacing. One-piece titanium alloy implants with a maximum diameter of 3.0 mm and a resorbable blast surface texture on a square-thread form were evaluated. Digital photographs were made at each clinical visit to assess soft tissue healing. Interproximal soft tissue fill of the embrasure was assessed with a modified Jemt index. Standardized radiographs were made at baseline (implant placement) and at 6 and 12 months postsurgery. Radiographic bone height was measured from a consistent landmark on the implant. A 1-sided t test was used to determine statistical differences of bone height. Thirty-one implants were placed in 17 subjects. One implant had clinical mobility and was removed, for an overall survival rate of 96.7%. Mean bone height on the day of placement and restoration was 2.33 + 0.73 mm above the first thread. Mean bone height was 1.75 +/- 0.78 mm at 6 months postrestoration and 1.63 +/- 0.81 mm at 12 months postrestoration. There was a statistically significant loss of bone support over the initial 6 months (0.58 mm; P < .01), with no significant progression thereafter (0.12 mm; NS). Complete fill of papillae was found in 92% of maxillary lateral incisor sites and 60% of mandibular incisor sites. The use of 1-piece narrow-diameter immediately loaded implants appears to be an effective prosthetic treatment for areas of limited space.


Video-assisted thoracic surgery for the management of pyothorax in dogs: 14 cases.
To report the perioperative findings and outcome of dogs undergoing video-assisted thoracic surgery (VATS) for the management of pyothorax. Multi-institutional, retrospective study. Client-owned dogs (n = 14). Medical records of dogs with pyothorax managed via VATS were reviewed for signalment, history, clinical signs, clinicopathological findings, diagnostic imaging results, surgical variables, bacterial culture and sensitivity results, post-operative management and outcome. VATS was performed after placing a paraxyphoid endoscopic portal and 2-3 intercostal instrument portals. VATS exploration was followed by one or more of the following: mediastinal debridement, tissue sampling, pleural lavage, and placement of a thoracostomy tube. Two dogs (14%) required conversion from VATS to an open thoracotomy to completely resect proliferative mediastinal tissue. These dogs had severe pleural effusion on preoperative thoracic radiographs and one had severely thickened contrast-enhancing mediastinum on preoperative computed tomography (CT). The cause of pyothorax was identified as a penetrating gastric foreign body (n = 2), migrating plant material (n = 2), and idiopathic (n = 10). The median follow-up time was 143 days (range, 14-2402 days). All dogs were discharged from the hospital and their clinical signs resolved. One patient had recurrence of a pyothorax requiring revision surgery 17 months postoperatively. VATS allows minimally invasive treatment of uncomplicated canine pyothorax. Preoperative thoracic CT may help identify candidates for VATS among dogs with pyothorax.


"Without Compassion We Don't Have a Social Work Field": A Thematic Analysis Exploring Social Workers' Experiences with Compassion.
Evidence establishing the importance of compassion in the context of social work practice is emerging. Compassion, stemming from the Latin words com and pati, means to suffer with. Given the proximity social workers have to vast experiences of suffering, compassion may play a central role in providing meaningful care to individuals, communities, and systems. The purpose of this qualitative study was to explore social workers' definitions of and experiences with compassion. Participants included 12 social workers working across levels of practice in two Midwestern states in the United States. Data were collected via semi-structured interviews. Thematic analysis demonstrated three themes present in the data. Consistent with previous conceptual scholarship, the findings illustrated that compassion is a central component of social work practice. Additionally, results from the study demonstrated that social workers find compassion to be an imperative component of ethical practice and suggested that both barriers to and facilitators of compassion are present across levels of social work practice. This study adds to the growing body of social work scholarship exploring compassion and highlights implications for the social work discipline across levels of practice to more overtly center compassion in education, practice, and policy. Further research is needed to better understand multilevel barriers to compassion and develop strategies for overcoming them. Moreover, additional research is needed to holistically understand how to leverage and build upon the facilitators of compassion identified by participants in order to foster compassionate social workers, social work organizations, and systems.


[Urate urolithiasis: efficacy of combined treatment with trometamol compositum].
Contact dissolution of urate concrements was assessed in a direct action of the drug trometamol compositum on a concrement in combination with modem low-invasive technologies. A total of 67 patients with urate urolithiasis were divided into two groups: 44 patients of group 1 have undergone contact litholysis, 23 patients of group 2 have undergone extracorporeal shock-wave lithotripsy followed by contact litholysis. Dissolution was made with the drug trometamol compositum (Berlin-Chemie, Germany) delivered antegradely through nephrostomic drainage made previously. Other important components of litholysis consisted in low-intensive laser radiation and prophylactic antibacterial therapy. Positive results were achieved in all the patients. Mean litholysis duration was 4.8 +/- 1.8 days in group 1 and 1.09 +/- 0.29 days in group 2. Thus, high efficacy of the method is demonstrated.


Multiple sites of highly amplified DNA sequences detected by molecular cytogenetic analysis in HS-RMS-2, a new pleomorphic rhabdomyosarcoma cell line.
A molecular cytogenetic analysis was performed on HS-RMS-2, a cell line established in this laboratory from a rare pleomorphic type of rhabdomyosarcoma. G-banding and multicolor-FISH analyses revealed that the cells have a complex chromosomal composition. Comparative genomic in situ hybridization (CGH) detected eight highly amplified regions at 1p36.1-p36.2, 1p31-p32, 1q21-q31, 8q12-q21, 8q24-qter, 11q12-q13, 12q13-q14 and 18q12-q22, suggesting the co-existence of multiple amplified oncogenes in these tumor cells. Reverse chromosome painting, using a probe regenerated by microdissection of a long marker chromosome, revealed the native location of three of eight possible genes to be on chromosomes 1p31-32, 12q14 and 18q21. FISH using BAC and cosmid probes revealed amplification of JUN (1p31), MYC (8q24), CCND1 (11q13), INT2 (11q13.3), MDM2 (12q14.3-q15) and MALT (18q21). These findings indicate that at least eight amplified oncogenes may contribute to the pathogenesis of a rare pleomorphic type of rhabdomyosarcoma. This new cell line should prove useful for in vitro preclinical studies of molecularly targeted therapies.


The use of person-organization fit in employment decision making: an assessment of its criterion-related validity.
Because measures of person-organization (P-O) fit are accountable to the same psychometric and legal standards used for other employment tests when they are used for personnel decision making, the authors assessed the criterion-related validity of P-O fit as a predictor of job performance and turnover. Meta-analyses resulted in estimated true criterion-related validities of .15 (k = 36, N = 5,377) for P-O fit as a predictor of job performance and .24 (k = 8, N = 2,476) as a predictor of turnover, compared with a stronger effect of .31 (k = 109, N = 108,328) for the more commonly studied relation between P-O fit and work attitudes. In contrast to the relations between P-O fit and work attitudes, the lower 95% credibility values for the job performance and turnover relations included zero. In addition, P-O fit's relations with job performance and turnover were partially mediated by work attitudes. Potential concerns pertaining to the use of P-O fit in employment decision making are discussed in light of these results.


Improvement in Care and Outcomes for Emergency Medical Service-Transported Patients With ST-Elevation Myocardial Infarction (STEMI) With and Without Prehospital Cardiac Arrest: A Mission: Lifeline STEMI Accelerator Study.
Patients with ST-elevation myocardial infarction (STEMI) with out-of-hospital cardiac arrest (OHCA) may benefit from direct transport to a percutaneous cardiac intervention (PCI) hospital but have previously been less likely to bypass local non-PCI hospitals to go to a PCI center. We reported time trends in emergency medical service transport and care of patients with STEMI with and without OHCA included from 171 PCI-capable hospitals in 16 US regions with participation in the Mission: Lifeline STEMI Accelerator program between July 1, 2012, and March 31, 2014. Time trends by quarter were assessed using logistic regression with generalized estimating equations to account for hospital clustering. Of 13 189 emergency medical service-transported patients, 88.7% (N=11 703; 10.5% OHCA) were taken directly to PCI hospitals. Among 1486 transfer-in patients, 21.7% had OHCA. Direct transport to a PCI center for OHCA increased from 74.7% (July 1, 2012) to 83.6% (March 31, 2014) (odds ratio per quarter, 1.07; 95% confidence interval, 1.02-1.14), versus 89.0% to 91.0% for patients without OHCA (odds ratio, 1.03; 95% confidence interval, 0.99-1.07; interaction P=0.23). The proportion with prehospital ECGs increased for patients taken directly to PCI centers (53.9%-61.9% for those with OHCA versus 73.9%-81.9% for those without OHCA; interaction P=0.12). Of 997 patients with OHCA taken directly to PCI hospitals and treated with primary PCI, first medical contact-to-device times within the guideline-recommended goal of ≤90 minutes were met for 34.5% on July 1, 2012, versus 41.8% on March 31, 2014 (51.6% and 56.1%, respectively, for 9352 counterparts without OHCA; interaction P=0.72). Direct transport to PCI hospitals increased for patients with STEMI with and without OHCA during the 2012 to 2014 Mission: Lifeline STEMI Accelerator program. Proportions with prehospital ECGs and timely reperfusion increased for patients taken directly to PCI hospitals.


Genomic survey of candidate stress-response genes in the estuarine anemone Nematostella vectensis.
Salt marshes are challenging habitats due to natural variability in key environmental parameters including temperature, salinity, ultraviolet light, oxygen, sulfides, and reactive oxygen species. Compounding this natural variation, salt marshes are often heavily impacted by anthropogenic insults including eutrophication, toxic contamination, and coastal development that alter tidal and freshwater inputs. Commensurate with this environmental variability, estuarine animals generally exhibit broader physiological tolerances than freshwater, marine, or terrestrial species. One factor that determines an organism's physiological tolerance is its ability to upregulate "stress-response genes" in reaction to particular stressors. Comparative studies on diverse organisms have identified a number of evolutionarily conserved genes involved in responding to abiotic and biotic stressors. We used homology-based scans to survey the sequenced genome of Nematostella vectensis, the starlet sea anemone, an estuarine specialist, to identify genes involved in the response to three kinds of insult-physiochemical insults, pathogens, and injury. Many components of the stress-response networks identified in triploblastic animals have clear orthologs in the sea anemone, meaning that they must predate the cnidarian-triploblast split (e.g., xenobiotic receptors, biotransformative genes, ATP-dependent transporters, and genes involved in responding to reactive oxygen species, toxic metals, osmotic shock, thermal stress, pathogen exposure, and wounding). However, in some instances, stress-response genes known from triploblasts appear to be absent from the Nematostella genome (e.g., many metal-complexing genes). This is the first comprehensive examination of the genomic stress-response repertoire of an estuarine animal and a member of the phylum Cnidaria. The molecular markers of stress response identified in Nematostella may prove useful in monitoring estuary health and evaluating coastal conservation efforts. These data may also inform conservation efforts on other cnidarians, such as the reef-building corals.


Cardiology in a district hospital.
During 1975-81 a non-invasive cardiac unit was established at St Peter's Hospital, Chertsey, a district hospital serving a population of 202 000. There was a progressive increase in outpatient referrals in cardiology, and in 1981 non-invasive investigations included 424 echocardiograms, 305 exercise electrocardiograms, 275 ambulatory electrocardiograms, and 147 thallium-201 studies. Between 1979 and 1981, 151 patients were admitted directly to major centres for further investigation; 74% of those with ischaemic heart disease and 68% of those with valvular heart disease subsequently underwent surgery, a ratio of investigation to surgery that is half the norm for the four metropolitan regions. Based on the 1981 figures, which were substantially above those for 1980, there is a need for a minimum of 270 open heart operations per million of the population including 180 vein bypass operations. This figure for bypass grafting is 230% higher than in the United Kingdom as a whole in 1978 and has substantial implications.


Reconstruction of contaminant trends in a salt wedge estuary with sediment cores dated using a multiple proxy approach.
The Taunton River is a partially mixed tidal estuary in southeastern Massachusetts (USA) which has received significant contaminant inputs, yet little information exists on the history of discharge and the subsequent fate of these contaminants. Three sediment cores taken along a transect were analyzed, reconstructing the spatial and temporal trends of pollution in the estuary. A combination of radiometric dating, contaminant markers, and storm layers from major hurricanes were used to establish age models and sedimentation rates. Age estimates obtained from the different dating methods compared well, establishing an accurate history of contaminant release to the estuary. Polycyclic aromatic hydrocarbons (PAHs) were present in one core at depths corresponding to the early 1860s, earlier than previously established dates of introduction. Temporal and spatial trends of Cr, Cu, Hg and Pb indicated multiple sources of varying input to the river. Polychlorinated biphenyls (PCBs) were present in each of the cores from the 1930s onward, with elevated levels still present in surficial sediments at several sites. A unique organic compound, Topanol, which was produced locally was used as a tracer to track contaminant transport in the river. Tracer data indicates that contaminants are still being transported and deposited to surficial sediments at high concentrations well after their discharge. This reconstruction demonstrates the utility of using multiple dating proxies where often the sole use of radiometric dating techniques is not an option and provides insights into the fate of contaminants discharged decades ago but continue to represent environmental risks.


Conversion of a plant oxidosqualene-cycloartenol synthase to an oxidosqualene-lanosterol cyclase by random mutagenesis.
A random mutagenesis/in vivo selection approach was applied to generate and identify mutations that alter the product specificity of oxidosqualene-cycloartenol synthase (CAS) from Arabidopsis thaliana. This work complements previous studies of triterpene cyclase enzymes and was undertaken to provide knowledge of the frequency and locations at which point mutations can alter cyclase product specificity. Random mutations were introduced by treatment with hydroxylamine or passage through a mutator strain of bacteria. Libraries of mutated plasmids carrying the cas1 gene were transformed into a cyclase-deficient strain of Saccharomyces cerevisiae (CBY57) bearing a complementing plasmid (pZS11) carrying an Erg7 gene that encodes wild-type yeast oxidosqualene-lanosterol cyclase and a URA3 marker that could be counterselected by growth in media containing 5-fluoroorotic acid (5-FOA). This allowed use of a plasmid shuffle to select for cas1 mutants that could substitute for ERG7 activity. Five of approximately 73,000 transformants were observed to grow in media containing 5-FOA but lacking ergosterol. pTKP5-derived plasmids isolated from these transformants were sequenced, revealing five distinct and unique point mutations: Tyr410Cys, Ala469Val, His477Tyr, Ile481Thr, and Tyr532His. Analysis of the nonsaponifiable lipids from CBY57 cells expressing these mutants suggests that the Tyr410Cys and His477Tyr mutants produce lanosterol as the dominant product, whereas the Ala469Val, Ile481Thr, and Tyr532His mutants produce a mixture of lanosterol and achilleol A, a product of monocyclization. Sequence and structural homology modeling of CAS indicate that the observed product specificity-altering mutations occur both within (Tyr410Cys, Ile481Thr, and Tyr532His) and outside of (Ala469Val and His477Tyr) the cyclase active site.


Mitochondrial DNA, human evolution and the cancer genotype.
Mitochondrial DNA is a small, well characterized chromosome which is transmitted across the generations in the maternal lineage, independently of nuclear DNA. mtDNA acts in effect as a robust, species specific biological clock and tracer which can be used to follow the evolution and spread by geographic migration of populations from their origins. Mutations in mtDNA cause specific maternally hereditable diseases, and can be used for forensic purposes. They are not specifically implicated in neoplasia, but they may provide clues as to the nature and origins of cancer susceptibility in various populations.


Design of broadband RF pulses with polynomial-phase response.
The achievable bandwidth of common linear-phase RF pulses is limited by the maximum feasible B1 amplitude of the MR system. It has been shown previously, that this limitation can be circumvented by overlaying a quadratic phase in the frequency domain, which spreads the power across the pulse duration. Quadratic-phase RF pulses are near optimal in terms of achieving minimal B1max. In this work, it is demonstrated that further B1max reduction can be achieved by combining quadratic with higher-order polynomial-phase functions. RF pulses with a phase response up to tenth order were designed using the Shinnar-Le Roux transformation, yielding considerable increases in bandwidth and selectivity as compared to pure quadratic-phase pulses. These benefits are studied for a range of pulse specifications and demonstrated experimentally. For B1max = 20 microT and a pulse duration of 2.1 ms, it was possible to increase the bandwidth from 3.1 kHz for linear and 3.8 kHz for a quadratic to 9.9 kHz for a polynomial-phase pulse.


Incapacitating hypersensitivity to one's own body sounds due to a dehiscence of bone overlying the superior semicircular canal. A case report.
We present a case study of a 49-year-old patient with an 8-year history of hypersensitivity to sound produced by intrinsic but not extrinsic sources. Findings that indicated an organic problem were: a supranormal bone conduction threshold of -25 to -15 dB HL from 0.25 to 1 kHz with an air-bone gap of 15 to 45 dB HL, a lower threshold and larger amplitude for vestibular-evoked myogenic potentials, eye movement reactions to sound and trunk pitch sway in response to sound. Results of immitance audiometry and otoacoustic emission testing were within normal limits and indicative of intact middle ear conductance. A high-resolution CT scan of the temporal bone demonstrated a dehiscence of bone overlying the superior semicircular canal. These findings support previous research indicating that auditory energy reaches the cochleo-vestibular receptor systems more easily via transmission through cerebrospinal fluid than through bone. Therefore, a dehiscence of the bone overlying the superior semicircular canal may lead to hypersensitivity to intrinsic sound. We recommend that similar findings in other patients be followed up with an evaluation of middle ear function and the temporal bone with high-resolution CT scan.


What motivates general practitioners to change practice behaviour? A qualitative study of audit and feedback group sessions in Dutch general practice.
Adopting an attributional perspective, the current article investigates how audit and feedback group sessions contribute to general practitioners' (GPs) motivation to change their practice behaviour to improve care. We focus on the contributions of the audit and feedback itself (content) and the group discussion (process). Four focus groups, comprising a total of 39 participating Dutch GPs, discussed and compared audit and feedback of their practices. The focus groups were analysed thematically. Audit and feedback contributed to GPs' motivation to change in two ways: by raising awareness about aspects of their current care practice and by providing indications of the possible impact of change. For these contributions to play out, the audit and feedback should be reliable and valid, specific, recent and recurrent and concern GPs' own practices or practices within their own influence sphere. Care behaviour attributed to external, uncontrollable or unstable causes would not induce change. The added value of the group is twofold as well: group discussion contributed to GPs' motivation to change by providing a frame of reference and by affording insights that participants would not have been able to achieve on their own. In audit and feedback group sessions, both audit and feedback information and group discussion can valuably contribute to GPs' motivation to change care practice behaviour. Peer interaction can positively contribute to explore alternative practices and avenues for improvement. Local or regional peer meetings would be beneficial in facilitating reflection and discussion. An important avenue for future studies is to explore the contribution of audit and feedback and small-group discussion to actual practice change.


Glutathione-responsive disassembly of disulfide dicyanine for tumor imaging with reduction in background signal intensity.
Near-infrared (NIR) fluorescence imaging has been proved as an effective modality in identifying the tumor border and distinguishing the tumor cells from healthy tissue during the oncological surgery. Developing NIR fluorescent probes with high tumor to background (T/B) signal is essential for the complete debulking of the tumor, which will prolong the survival rate of tumor patients. However, the nonspecific binding and "always-on" properties of the conventional fluorescent probes leads to high background signals and poor specificity. Method: To address this problem, glutathione (GSH)-responsive, two disulfide-bonded dicyanine dyes (ss-diCy5 and ss-diNH800CW) were synthesized. As synthesized dyes are quenched under normal physiological conditions, however, once reached to the tumor site, these dyes are capable of emitting strong fluorescence signals primarily because of the cleavage of the disulfide bond in the tumor microenvironment with high GSH concentration. Besides, the GSH-responsive behavior of these dyes was monitored using the UV-vis and fluorescence spectroscopy. The diagnostic accuracy of the aforementioned dyes was also tested both in tumor cells and 4T1-bearing mice. Results: The fluorescence signal intensity of disulfide dicyanine dyes was quenched up to 89% compared to the mono cyanine dyes, thus providing a very low fluorescence background. However, when the disulfide dicyanine dye reaches the tumor site, the dicyanine is cleaved by GSH into two mono-dyes with high fluorescence strength, thus producing strong fluorescent signals upon excitation. The fluorescent signal of the dicyanine was enhanced by up to 27-fold after interacting with the GSH solution. In vivo xenografts tumor studies further revealed that the fluorescence signals of aforementioned dyes can be quickly recovered in the solid tumor. Conclusion: In summary, the disulfide dicyanines dyes can provide a promising platform for specific tumor-activatable fluorescence imaging with improved T/B value.


Five-year obesity incidence in the transition period between adolescence and adulthood: the National Longitudinal Study of Adolescent Health.
No nationally representative longitudinal data have been analyzed to evaluate the incidence of obesity in the transition between adolescence and adulthood. The objective was to examine dynamic patterns of change in obesity among white, black, Hispanic, and Asian US teens as they transitioned to young adulthood. We used nationally representative, longitudinally measured height and weight data collected from US adolescents enrolled in wave II (1996; ages 13-20 y) and wave III (2001; 19-26 y) of the National Longitudinal Study of Adolescent Health (n = 9795). Obesity incidence was defined on the basis of International Obesity Task Force (IOTF) cutoffs (wave II), which link childhood body mass index (BMI) centiles to adult cutoffs (BMI > or = 30; wave III), for comparability between adolescence and adulthood. In addition, the more commonly used cutoff of BMI > or = 95th percentile for age- and sex-specific cutoffs from the 2000 Centers for Disease Control and Prevention growth charts for adolescents (wave II) were compared with adult cutoffs (BMI > or = 30; wave III). On the basis of the IOTF cutoffs, obesity incidence over the 5-y study period was 12.7%; 9.4% of the population remained obese and 1.6% shifted from obese to nonobese. Obesity incidence was especially high in non-Hispanic black (18.4%) females relative to white females. The prevalence of obesity increased from 10.9% in wave II to 22.1% in wave III, and extreme obesity was 4.3% at wave III on the basis of a BMI > or = 40. During a 5-y transitional period between adolescence and young adulthood, the proportion of adolescents becoming and remaining obese into adulthood was very high. This upward trend is likely to continue. Effective preventive and treatment efforts are critically needed.


[Experimental rat model for fetal growth restriction: effects on liver glycogen and intestinal and renal morphometry].
to evaluate the effectiveness of the IUGR model by uterine artery ligation mimicking placental insufficiency in rats. sprague-Dawley rat fetuses were divided into three groups: IUGR (intrauterine growth restriction), with fetuses in the right horn of pregnant rats subjected to right uterine artery ligation at 18.5 days of gestation (term = 22 days); C-IUGR (control of restriction), with control fetuses in the left horn, and EC (external control), with fetuses of intact rats. Animals were harvested by cesarean section at day 21.5 days of gestation. Fetuses were weighed and then sacrificed. The intestine, liver, kidney and placenta were weighed and dissected for morphometric and histological analysis. the morphometric data showed decreased body weight (BW), liver weight (LW) and intestinal weight (IW) of fetuses with IUGR compared to C-IUGR and EC (p<0.001). The placental weight (PW), renal weight (RW) and LW/BW, IW/BW, and RW/BW ratios did not change. IUGR fetuses had decreased kidney thickness (p<0.001) and decreased thickness of the intestinal mucosa and submucosa (p<0.05). Histological evaluation showed reduction of liver glycogen storage in fetuses with IUGR compared to C-IUGR and CE. the model described was efficient and caused symmetric fetal IUGR with decreased size of most organs, especially the liver, and changes in glycogen stores.


Cost-effectiveness of a mobile technology-enabled primary care intervention for cardiovascular disease risk management in rural Indonesia.
Cardiovascular diseases (CVD) are the leading cause of death in Indonesia, and there are large disparities in access to recommended preventative treatments across the country, particularly in rural areas. Technology-enabled screening and management led by community health workers have been shown to be effective in better managing those at high risk of CVD in a rural Indonesian population; however, the economic impacts of implementing such an intervention are unknown. We conducted a modelled cost-effectiveness analysis of the SMARThealth intervention in rural villages of Malang district, Indonesia from the payer perspective over a 10-year period. A Markov model was designed and populated with epidemiological and cost data collected in a recent quasi-randomized trial, with nine health states representing a differing risk for experiencing a major CVD event. Disability-Adjusted Life Years (DALYs) were estimated for the intervention and usual care using disability weights from the literature for major CVD events. Annual treatment costs for CVD treatment and prevention were $US83 under current care and $US144 for those receiving the intervention. The intervention had an incremental cost-effectiveness ratio of $4288 per DALY averted and $3681 per major CVD event avoided relative to usual care. One-way and probabilistic sensitivity analyses demonstrated that the results were robust to plausible variations in model parameters and that the intervention is highly likely to be considered cost-effective by decision-makers across a range of potentially acceptable willingness to pay levels. Relative to current care, the intervention was a cost-effective means to improve the management of CVD in this rural Indonesian population. Further scale-up of the intervention offers the prospect of significant gains in population health and sustainable progress toward universal health coverage for the Indonesian population.


Peritonitis due to Staphylococcus sciuri in a patient on continuous ambulatory peritoneal dialysis.
Among the coagulase-negative staphylococci, Staphylococcus sciuri has rarely been described as the aetiology of continuous ambulatory peritoneal dialysis (CAPD) peritonitis. It has been reported in 1 case of endocarditis and has been isolated from peritoneal dialysis fluid in 2 patients. The case reported here describes CAPD peritonitis due to S. sciuri shortly after a previous episode due to S. aureus, showing the necessity to identify coagulase-negative staphylococci to find new species that cause CAPD peritonitis.


Comparative Analysis of the Liquid CO2 Washing with Conventional Wash on Firefighters' Personal Protective Equipment (PPE).
Firefighters are exposed to several potentially carcinogenic fireground contaminants. The current NFPA 1851 washing procedures are less effective in cleaning due to the limited intensity of the washing conditions that are used. The 2020 edition of NFPA 1851 has added limited specialized cleaning for higher efficacy. The liquid carbon dioxide (CO2) laundering technique has gained popularity in recent years due to its availability to remove contaminants and its eco-friendliness. The primary aim of this study is to address the firefighter questions regarding the efficacy of cleaning with liquid CO2 and to compare it with the conventional washing technique. The unused turnout jackets were contaminated with a mixture of fireground contaminants. These turnout jackets were cleaned with conventional NFPA 1851-appoved aqueous washing and a commercially available liquid CO2 method. Post-cleaning samples were analyzed for contamination using pressurized solvent extraction and GC-MS. The liquid CO2 technique demonstrated considerable improvement in washing efficiency compared to the conventional washing.


The impact of new national guidelines on screening for gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) has important maternal and fetal implications. In 2010, the Health Service Executive published guidelines on GDM. We examined the impact of the new guidelines in a large maternity unit. In January 2011, the hospital replaced the 100 g Oral Glucose Tolerance Test (OGTT) with the new 75 g OGTT. We compared the first 6 months of 2011 with the first 6 months of 2010. The new guidelines were associated with a 22% increase in women screened from 1375 in 2010 to 1679 in 2011 (p < 0.001). Of the women screened, the number diagnosed with GDM increased from 10.1% (n=139) to 13.2% (n=221) (p<0.001).The combination of increased screening and a more sensitive OGTT resulted in the number of women diagnosed with GDM increasing 59% from 139 to 221 (p = 0.02).This large increase has important resource implications but, if clinical outcomes are improved, there should be a decrease in long-term costs.


Rapid sequence divergence in mammalian beta-defensins by adaptive evolution.
beta-Defensin genes encode broad spectrum antimicrobial cationic peptides. We have analysed the largest murine and human clusters of these genes, which localise to mouse and human chromosome 8. Using hidden Markov models, we identified novel mouse and human beta-defensin genes. We subsequently found full-length expressed transcripts for these novel genes. Expression in the mouse was high in brain and reproductive tissues. Fourteen murine beta-defensins could be grouped into two clear sub-groups by virtue of their position and high signal sequence (exon 1 encoded) identity. In contrast, there was a very low level of sequence conservation in the exon 2 region encoding the mature antimicrobial peptide. Evolutionary analysis revealed strong evidence that following gene duplication, exon 1 and surrounding non-coding DNA show little divergence within subfamilies. The focus for rapid sequence divergence is localised in the DNA encoding the mature peptide and this is driven by accelerated positive selection. In the human we also conclude that the locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes prior to human-baboon divergence. This mechanism of adaptive evolution is consistent with the role of this gene family as defence against bacterial pathogens. In order to look at function of these rapidly evolving genes, we characterised one of the novel mouse beta-defensin genes. This gene deviates from the canonical six cysteine motif present in the mature functional peptide of all other beta defensins. This defensin related gene (Defr1) is most highly expressed in testis and heart and the genomic organisation is highly similar to Defb3-6. A synthetic Defr1 peptide was shown to exist as a dimer and yet displayed both antimicrobial and chemotactic activity. The antimicrobial activity of Defr1 against S. aureus, E. coli and B. cepacia was found to be reduced in raised concentration of NaCl, but its action against P. aeruginosa was independent of NaCl concentration. These data have major implications on the structure and functions of these important host defence molecules.


Noninvasive methods to evaluate bladder obstruction in men.
Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) commonly affect older men. Fifty percent of men in their sixties and 80% of men in their nineties will be affected. Many of these men will seek care for their bothersome symptoms and decreased quality of life. There is a poor association between LUTS and objective measures such as post void residual, voided volumes, or maximal flow. Pressure flow studies are considered the gold standard for detecting bladder outlet obstruction. These studies tend to be cumbersome, expensive, and have exposure to ionizing radiation. There are several techniques which may offer noninvasive methods of detecting bladder outlet obstruction (BOO) in men.


Dodecyl-β-melibioside Detergent Micelles as a Medium for Membrane Proteins.
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.


Activated charcoal and the absorption of ferrous sulfate in rats.
The treatment of iron poisoning has typically not included the administration of activated charcoal due to the lack of evidence supporting its efficacy. Several in vitro studies have demonstrated good adsorption of iron in a variety of pH ranges that were comparable to those found with other drugs for which activated charcoal is clinically used. This study was designed to determine whether activated charcoal altered the gastrointestinal absorption of toxic doses of iron as ferrous sulfate in an in vivo model. Seventy-five male Sprague-Dawley rats were randomly assigned into 5 groups: control given only distilled water; 100 mg elemental Iron and water; 1:1 charcoal to iron; 2:1 charcoal to iron; and 4:1 charcoal to iron. All treatments were administered consecutively by gavage within 5 min. Physiological measurements and blood samples were taken at 0, 1, 4 and 8 h after treatment. There were no consistent differences in physiological measurements among the 5 groups. Mean serum iron concentrations did not differ among Groups 2, 3, 4 and 5 at the 4 sampling times except at I h between Groups 4 and 5. The area under the curve for serum iron concentrations did not differ among the treatment groups. Activated charcoal did not alter the extent of iron absorption in the experimental model.


Combining a positive expiratory pressure device with a metered-dose inhaler reservoir system using chlorofluorocarbon albuterol and hydrofluoroalkane albuterol: effect on dose and particle size distributions.
Combining a positive expiratory pressure (PEP) device with inhalation of albuterol via metered dose inhaler (MDI) may improve drug delivery to the lung, but may also affect dose availability. Determine the effect of interposing a PEP device on dose availability of albuterol via MDI and reservoir with either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant. MDI dose availability of CFC albuterol (Proventil) and HFA albuterol (Proventil HFA) using an Aerosol Cloud Enhancer (ACE) reservoir with and without a PEP device (TheraPEP) attached was determined. Drug availability was assessed using an Andersen 8-stage cascade impactor operated at 28.3 +/- 0.5 L/min. The PEP device was inserted between the reverse-firing ACE and the United States Pharmacopeia induction throat. Drug collected on impactor plates was analyzed spectrophotometrically at 276 nm, and the fine particle fraction was determined as the mass of drug < 4.7 microns. With CFC albuterol, total dose and drug mass < 4.7 microns (means and standard deviations) for the MDI-ACE alone were 44.4 +/- 7.7 micrograms and 33.4 +/- 2.2 micrograms, respectively, and for the MDI-ACE with TheraPEP were 50.1 +/- 6.4 micrograms and 39.8 +/- 14.3 micrograms, respectively. With HFA-albuterol sulfate, total drug and drug mass < 4.7 microns for the MDI-ACE alone, expressed as base drug, were 41.7 +/- 4.2 micrograms and 35.2 +/- 6.3 micrograms, respectively, and for the MDI-ACE with TheraPEP were 48.9 +/- 8.0 micrograms and 44.2 +/- 6.2 micrograms, respectively. There was no significant difference in dose availability between the MDI-ACE alone and with the PEP device attached (Wilcoxon signed-rank test, p > 0.05), for either CFC or HFA albuterol. Interposing the TheraPEP device at the MDI-ACE outlet does not change total dose, drug mass < 4.7 microns, or mass median aerodynamic diameter of MDI albuterol, with either CFC or HFA propellants.


Pancreatic Polypeptide-Secreting Tumour of the Proximal Pancreas (PPoma)-Ultra Rare Pancreatic Tumour: Clinically Malign, Histologically Benign.
Background and objectives: Here we report a rare case of a pancreatic polypeptide-secreting tumour (PPoma) discovered by accident during an autopsy. These PPomas occur in less than 2% of all pancreatic neoplasms and are almost exclusively silent, i.e., they are non-functional. Symptoms arising from PPoma are due to its compression of surrounding tissue. Materials and methods: The autopsy was performed on a 68-year-old male diagnosed with multiple endocrine neoplasm type 1 (MEN1) due to the patient's sudden death. Results: A solitary, densely fibrotic, pink-brown tumour, 18 mm in size tumorous mass, was localised in the head of the pancreas. Microscopically, the tumour had a glandular structure with a tubuloacinar arrangement of the cells. Immunohistochemically, we detected strong PP (pancreatic polypeptide) intracytoplasmic activity and negative glucagon activity. The PPoma was located in the head of the pancreas, likely resulting in the obstruction of the main pancreatic and common bile duct. Conclusions: To the best of our knowledge, this is the first report suggesting the association of PPomas with MEN1. Also, the PPoma could be the cause of acute hemorrhagic pancreatitis due to its location.


Mersilene suture as a vehicle for delivery of growth factors in tendon repair.
Extensive clinical and laboratory studies have demonstrated that growth factors accelerate and modulate the wound-healing process. The purpose of this experiment was to apply the principles of growth factor-enhanced wound healing to an in vitro rat tendon model. A method was developed for covalently binding a biologically active peptide to nonabsorbable braided polyester suture (Mersilene). Sutures were treated with various growth factors, which included epidermal growth factor, platelet-derived growth factor, and keratinocyte growth factor, and bovine serum albumin was the control. Spectrophotometric assessment was used to verify the peptide's activity. The suture was subsequently placed through individual harvested rat flexor tendons, which were arranged in standard tissue culture conditions. Markedly increased cellular proliferation along the suture was appreciated on the tendons treated with epidermal growth factor-bound suture. Platelet-derived growth factor was shown to have a lesser effect, whereas keratinocyte growth factor had no visible effect on cellular proliferation. This preliminary study describes a new technique of binding growth factors to suture. It also demonstrates that the presence of growth factors may help facilitate flexor tendon healing and allow early postoperative rehabilitation to decrease adhesion formation.


Comparison of sample types from white-tailed deer (Odocoileus virginianus) for DNA extraction and analyses.
Collection of biological samples for DNA is necessary in a variety of disciplines including disease epidemiology, landscape genetics, and forensics. Quantity and quality of DNA varies depending on the method of collection or media available for collection (e.g., blood, tissue, fecal). Blood is the most common sample collected in vials or on Whatman Flinders Technology Associates (FTA) cards with short- and long-term storage providing adequate DNA for study objectives. The focus of this study was to determine if biological samples stored on Whatman FTA Elute cards were a reasonable alternative to traditional DNA sample collection, storage, and extraction. Tissue, nasal swabs, and ocular fluid were collected from white-tailed deer (Odocoileus virginianus). Tissue samples and nasal swabs acted as a control to compare extraction and DNA suitability for microsatellite analysis for nasal swabs and ocular fluid extracted from FTA Elute cards. We determined that FTA Elute cards improved the extraction time and storage of samples and that nasal swabs and ocular fluid containing pigmented fluid were reasonable alternatives to traditional tissue DNA extractions.


Completion of meiosis in male zebrafish (Danio rerio) despite lack of DNA mismatch repair gene mlh1.
Mlh1 is a member of DNA mismatch repair (MMR) machinery and is also essential for the stabilization of crossovers during the first meiotic division. Recently, we have shown that zebrafish mlh1 mutant males are completely infertile because of a block in metaphase I, whereas females are fertile but have aneuploid progeny. When studying fertility in males in a two-fold more inbred background, we have however observed low numbers of fertilized eggs (approximately 0.4%). Histological examination of the testis has revealed that all spermatogenic stages prior to spermatids (spermatogonia, primary spermatocytes, and secondary spermatocytes) are significantly increased in the mutant, whereas the total weight of spermatids and spermatozoa is highly decreased (1.8 mg in wild-type vs. 0.1 mg in mutants), a result clearly different from our previous study in which outbred males lack secondary spermatocytes or postmeiotic cells. Thus, a delay of both meiotic divisions occurs rather than complete arrest during meiosis I in these males. Eggs fertilized with mutant sperm develop as malformed embryos and are aneuploid making this male phenotype much more similar to that previously described in the mutant females. Therefore, crossovers are still essential for proper meiosis, but meiotic cell divisions can progress without it, suggesting that this mutant is a suitable model for studying the cellular mechanisms of completing meiosis without crossover stabilization.


Effectiveness of lifestyle interventions for improving the physical health of children and adolescents taking antipsychotic medications: protocol for a systematic review and meta-analysis.
Children and adolescents are increasingly prescribed antipsychotic medications off-label in the treatment of behavioural disorders. While antipsychotic medications are effective in managing behavioural issues, they carry a significant risk of adverse events that compromise ongoing physical health. Of particular concern is the negative impact antipsychotic medications have on cardiometabolic health. Interventions that aim to modify lifestyle habits have the potential to alleviate the adverse effects of antipsychotic medication by enhancing weight management, increasing physical activity, promoting better nutritional practices, improving dietary habits and promoting healthier sleep patterns and sleep hygiene. However, a comprehensive review has not been performed to ascertain the effectiveness of lifestyle interventions for children and adolescents who are at increased risk of antipsychotic-induced compromises to their physical health. This systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Four databases will be searched without any year constraints to identify randomised controlled trials that are published in the English language and report a lifestyle intervention compared with usual care with any physical health outcome measure. Trial registers and results repositories will be scoured to identify additional studies. Two reviewers will independently conduct screening, data extraction and quality assessment and compare the results. Quantitative data will be synthesised, where appropriate, through a random-effects meta-analysis model. Otherwise, data will be reported in a qualitative (narrative) synthesis. Heterogeneity will be quantified using the I2 statistic. The Cochrane Risk of Bias 2 tool will be used for risk of bias assessment. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to evaluate the cumulative body of evidence. Ethics approval is not required. The publication plan will target high-impact, peer-reviewed journals that fall under the scope of Psychiatry and Mental Health. CRD42022380277.


Adalimumab for the treatment of Crohn's disease.
The advent of biologic therapy for Crohn's disease has revolutionized our approach to disease management and redefined our goals. Infliximab (Remicade), an intravenously delivered murine-chimeric monoclonal antibody against TNF-alpha was released in 1998 and shown to have significant benefits in patients with refractory luminal and fistulizing Crohn's disease. Since then other anti-TNF strategies have undergone investigation with variable results. Adalimumab (Humira), a self administered, subcutaneous, fully human monoclonal antibody against TNF-alpha represents the next generation of therapy. It has demonstrated efficacy for induction and maintenance of remission in patients with moderate-to-severe Crohn's in three large double-blind, placebo-controlled, randomized trials. In addition it has demonstrated steroid-sparing properties and the ability to reduce hospitalizations and improve quality of life. It is anticipated, given its clinical efficacy, its fully human nature, and the convenience of self administration that it will have a significant effect on the management of Crohn's disease.


Protocol for a feasibility exploratory multicentre study of factors influencing trauma patients' outcomes of traffic crashes in Saudi Arabia.
Road traffic injury is a leading cause of death for people of all ages. The burden of road traffic injuries is well established in developed countries. However, there has been limited investigation of the incidence and burden of road traffic injury in low/middle-income countries. With a proportionally high number of road users, there is a need to explore the factors in prehospital and hospital care in Saudi Arabia (SA) that are associated with mortality for adult trauma patients following road traffic crashes (RTCs). This paper outlines the method for the planned research. A feasibility exploratory multicentre study will be conducted at three purposefully selected hospitals with different trauma care resources in differing geographic locations of SA. The study sample will include all adult trauma patients who are involved in RTCs in SA and have been admitted to a study site in a 3-month period from May to July 2019. Data regarding the characteristics of the crashes and prehospital health care factors will be extracted from hospital databases where it is available. Information will be collected from patients or carers and hospital records in the two sites that do not have a registry. Patient status at 30 days post-injury, particularly mortality, will be assessed through hospital records. The relative contribution of a range of factors to predicting mortality will be explored using logistic regression analysis. This study was approved by the Institutional Review Board Committee at King Saud Medical City (H-01-R-053), the General Department of Research and Studies at the Ministry of Health in SA (1440-1249939) and (1440-1398648), and the La Trobe University Human Research Ethics Committee (HEC19095). The results will be reported in a thesis and in peer-reviewed journal articles and conference presentations.


Identifying cliques of convergent characters: concerted evolution in the cormorants and shags.
A phylogenetic tree comprising clades with high bootstrap values or other strong measures of statistical support is usually interpreted as providing a good estimate of the true phylogeny. Convergent evolution acting on groups of characters in concert, however, can lead to highly supported but erroneous phylogenies. Identifying such groups of phylogenetically misleading characters is obviously desirable. Here we present a procedure that uses an independent data source to identify sets of characters that have undergone concerted convergent evolution. We examine the problematic case of the cormorants and shags, for which trees constructed using osteological and molecular characters both have strong statistical support and yet are fundamentally incongruent. We find that the osteological characters can be separated into those that fit the phylogenetic history implied by the molecular data set and those that do not. Moreover, these latter nonfitting osteological characters are internally consistent and form groups of mutually compatible characters or "cliques," which are significantly larger than cliques of shuffled characters. We suggest, therefore, that these cliques of characters are the result of similar selective pressures and are a signature of concerted convergence.


A Novel qPCR Method for Simultaneous Detection and Quantification of Viable Pathogenic and Non-pathogenic Vibrio parahaemolyticus (tlh+ , tdh+ , and ureR + ).
Pathogenic and non-pathogenic Vibrio parahaemolyticus strains were simultaneously detected and quantified using a novel viable multiplex real-time PCR (novel qPCR). We used a new PCR primer and probe, ureR, as a surrogate for detection of the toxin trh gene as the primer was better at identifying variant V. parahaemolyticus trh strains. The specificity of all primers and probes used in this study were validated on three standard strains of V. parahaemolyticus, 42 clinical strains, 12 wild strains, 4 strains of Vibrio spp., and 4 strains of other bacteria. Then, propidium monoazide (PMA) was applied to inhibit DNA of dead cell, and the results of PMA optimized treatments were 15 μM concentration, 5 min incubation periods, 15 min light exposure periods and 30 RPM rotational speed, which resulted in time and cost savings. Pathogenic and non-pathogenic strains were quantified using a two-reaction tube method where the tlh, tdh, and ureR genes were amplified. Additionally, standard curves with a 7-log dynamic range were generated for quantifying viable V. parahaemolyticus and the amplification efficiencies were 108.68, 105.17, and 115.61% for tlh+ , tdh+ , and ureR + . This novel qPCR accurately monitored V. parahaemolyticus contamination rates in shrimps (Penaeus vannamei) and clams (Ruditapes philippinarum) sampled from retail stores located in a major district in Shanghai. In conclusion, our assay can prioritize the detection and quantification of viable pathogenic V. parahaemolyticus and can prove to be a more effective tool for reducing infection risks from consumption of seafood in Shanghai.


Euphorbia bicolor (Euphorbiaceae) Latex Extract Reduces Inflammatory Cytokines and Oxidative Stress in a Rat Model of Orofacial Pain.
Recent studies have reported that the transient receptor potential V1 ion channel (TRPV1), a pain generator on sensory neurons, is activated and potentiated by NADPH oxidase-generated reactive oxygen species (ROS). ROS are increased by advanced oxidation protein products (AOPPs), which activate NADPH oxidase by upregulating Nox4 expression. Our previous studies reported that Euphorbia bicolor (Euphorbiaceae) latex extract induced peripheral analgesia, partly via TRPV1, in hindpaw-inflamed male and female rats. The present study reports that E. bicolor latex extract also can evoke analgesia via reduction of oxidative stress biomarkers and proinflammatory cytokines/chemokines in a rat model of orofacial pain. Male and female rats were injected with complete Freund's adjuvant (CFA) into the left vibrissal pad to induce orofacial inflammation, and mechanical allodynia was measured by the von Frey method. Twenty-four hours later, rats received one injection of E. bicolor latex extract or vehicle into the inflamed vibrissal pad. Mechanical sensitivity was reassessed at 1, 6, 24, and/or 72 hours. Trigeminal ganglia and trunk blood were collected at each time point. In the trigeminal ganglia, ROS were quantified using 2',7'-dichlorodihydrofluorescein diacetate dye, Nox4 protein was quantified by Western blots, and cytokines/chemokines were quantified using a cytokine array. AOPPs were quantified in trunk blood using a spectrophotometric assay. E. bicolor latex extract significantly reduced orofacial mechanical allodynia in male and female rats at 24 and 72 hours, respectively. ROS, Nox4, and proinflammatory cytokines/chemokines were significantly reduced in the trigeminal ganglia, and plasma AOPP was significantly reduced in the trunk blood of extract-treated compared to vehicle-treated rats. In vitro assays indicate that E. bicolor latex extract possessed antioxidant activities by scavenging free radicals. Together our data indicate that the phytochemicals in E. bicolor latex may serve as novel therapeutics for treating oxidative stress-induced pain conditions.


Understanding Functional Redundancy and Promiscuity of Multidrug Transporters in E. coli under Lipophilic Cation Stress.
Multidrug transporters (MDTs) are major contributors to microbial drug resistance and are further utilized for improving host phenotypes in biotechnological applications. Therefore, the identification of these MDTs and the understanding of their mechanisms of action in vivo are of great importance. However, their promiscuity and functional redundancy represent a major challenge towards their identification. Here, a multistep tolerance adaptive laboratory evolution (TALE) approach was leveraged to achieve this goal. Specifically, a wild-type E. coli K-12-MG1655 and its cognate knockout individual mutants ΔemrE, ΔtolC, and ΔacrB were evolved separately under increasing concentrations of two lipophilic cations, tetraphenylphosphonium (TPP+), and methyltriphenylphosphonium (MTPP+). The evolved strains showed a significant increase in MIC values of both cations and an apparent cross-cation resistance. Sequencing of all evolved mutants highlighted diverse mutational mechanisms that affect the activity of nine MDTs including acrB, mdtK, mdfA, acrE, emrD, tolC, acrA, mdtL, and mdtP. Besides regulatory mutations, several structural mutations were recognized in the proximal binding domain of acrB and the permeation pathways of both mdtK and mdfA. These details can aid in the rational design of MDT inhibitors to efficiently combat efflux-based drug resistance. Additionally, the TALE approach can be scaled to different microbes and molecules of medical and biotechnological relevance.


Identification of molecular targets in vulvar cancers.
To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment. After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p-value≤0.05 indicating significance. Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS (n=1, respectively) and BRAF (n=2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA: exon 9 [E545K], RAS: G13D, Q61L, BRCA2: S1667X, BRAF: R443T, FBXW7: E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC (p-values all <0.05). Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.


A Modified Technique of Fixation for Proximal Femoral Valgus Osteotomy in Abnormal Bone: A Report of Two Cases.
The ideal size of intramedullary device to fix corrective osteotomy of proximal femur in abnormal bone in children and small patients may not be easily available. We report the successful use of Rush rod in combination with multiple Kirschner wires to fix the corrective osteotomy of coxa vara and shepherd crook deformity in two patients with osteogenesis imperfecta and fibrous dysplasia. The union was achieved on time, neck shaft angle and rotation were maintained.


Outer membrane localization of murein hydrolases: MltA, a third lipoprotein lytic transglycosylase in Escherichia coli.
Lytic transglycosylases are a unique lysozyme-like class of murein hydrolases believed to be important for growth of Escherichia coli. A membrane-bound lytic transglycosylase with an apparent molecular mass of 38 kDa, which was designated Mlt38, has previously been purified and characterized (A. Ursinus and J.-V. Höltje, J. Bacteriol. 176:338-343, 1994). On the basis of four tryptic peptides, the gene mltA was mapped at 63 min on the chromosomal map of E. coli K-12 and cloned by reverse genetics. The open reading frame was found to contain a typical lipoprotein consensus sequence, and the lipoprotein nature of the gene product was demonstrated by [3H]palmitate labeling. On the basis of the distribution of MltA in membrane fractions obtained by sucrose gradient centrifugation, a localization in the outer membrane is indicated. Overexpression of MltA at 30 degrees C, the optimal temperature for enzyme activity, but not at 37 degrees C results in the formation of spheroplasts. Not only a deletion mutant in mltA, but also double mutants in mltA and one of the two other well-characterized lytic transglycosylases (either sltY or mltB), as well as a triple mutant in all three enzymes, showed no obvious phenotype. However, dramatic changes in the structure of the murein sacculus indicate that lytic transglycosylases are involved in maturation of the murein sacculus.


Postoperative Oral Antibiotic Use and Infection-Related Complications After Spinal Cord Stimulator Surgery.
Spinal cord stimulation (SCS) is considered a minimally invasive and reversible neuromodulation therapy for various chronic pain disorders. The rates of infection following SCS surgery reported in the literature range from 2.8% to 10%. Several studies indicated no potential benefit of postoperative antibiotics (beyond 24 hours) on subsequent device infection. This study aimed to understand the characteristics of postoperative antibiotic prescriptions and subsequent infections following SCS surgery. The study was a retrospective cohort using the IBM® MarketScan® Commercial and Medicare Supplemental Databases from 2013 to 2018. Adult patients undergoing SCS surgical procedures with at least 90 days of follow-up were identified using Current Procedural Terminology (CPT®) codes. Postprocedural oral antibiotics within 14 days and preprocedural corticosteroid use within seven days were identified using National Drug Codes (NDC). Administrative claims were analyzed to understand the characteristics of prescribed postoperative antibiotics. Infection-related complications within 90 days were identified using administrative codes. A total of 18,105 patients (age 55.5 ± 13.1 years, 40.2% male) underwent SCS surgery during the study period. Postprocedural oral antibiotics and preprocedural steroids were prescribed for 35.3% and 2.6%, respectively, for SCS surgery patients. The most commonly used postprocedural antibiotics were cephalexin (55.4%) and sulfamethoxazole-trimethoprim (10.6%). The most common duration of antibiotic prescriptions was seven, ten, and five days in our study, from most to least common duration. Superficial surgical site infection (SSI), deep SSI, device infection, or any infection within 90 days occurred in 2.9%, 1.0%, 1.8%, and 4%, respectively, of the patients undergoing SCS surgery. Prospective studies are needed to understand the reasons for noncompliance with expert consensus recommendations on postoperative antibiotic use beyond 24 hours of SCS surgery. Neuromodulation team members should play an important role in antibiotic stewardship.


Methylation of the BRCA1 gene in sporadic breast cancer.
Mutations of the BRCA1 gene in tumor DNA from patients with sporadic breast cancer have not yet been observed. Nevertheless, BRCA1 activity is markedly decreased in invasive breast tumors. Previous reports have shown that hypermethylation of the promoter region is an alternative mechanism to mutation for the inactivation of tumor suppressor genes. We examined the BRCA1 promoter region for hypermethylation by Southern blotting. Hypermethylation was observed in two of seven sporadic breast carcinomas but not in any normal tissues. The hypermethylation was not an artifact because a control region was unmethylated in the two tumors. Although not all tumors were hypermethylated, these observations are consistent with an important role for epigenetic mechanisms in human cancer.


Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal.
We assess whether reactive oxygen species production and resistance to oxidative stress might be causally involved in the exceptional longevity exhibited by the ocean quahog Arctica islandica. We tested this hypothesis by comparing reactive oxygen species production, resistance to oxidative stress, antioxidant defenses, and protein damage elimination processes in long-lived A islandica with the shorter-lived hard clam, Mercenaria mercenaria. We compared baseline biochemical profiles, age-related changes, and responses to exposure to the oxidative stressor tert-butyl hydroperoxide (TBHP). Our data support the premise that extreme longevity in A islandica is associated with an attenuated cellular reactive oxygen species production. The observation of reduced protein carbonyl concentration in A islandica gill tissue compared with M mercenaria suggests that reduced reactive oxygen species production in long-living bivalves is associated with lower levels of accumulated macromolecular damage, suggesting cellular redox homeostasis may determine life span. Resistance to aging at the organismal level is often reflected in resistance to oxidative stressors at the cellular level. Following TBHP exposure, we observed not only an association between longevity and resistance to oxidative stress-induced mortality but also marked resistance to oxidative stress-induced cell death in the longer-living bivalves. Contrary to some expectations from the oxidative stress hypothesis, we observed that A islandica exhibited neither greater antioxidant capacities nor specific activities than in M mercenaria nor a more pronounced homeostatic antioxidant response following TBHP exposure. The study also failed to provide support for the exceptional longevity of A islandica being associated with enhanced protein recycling. Our findings demonstrate an association between longevity and resistance to oxidative stress-induced cell death in A islandica, consistent with the oxidative stress hypothesis of aging and provide justification for detailed evaluation of pathways involving repair of free radical-mediated macromolecular damage and regulation of apoptosis in the world's longest-living non-colonial animal.


An anionic synthetic sugar containing 6-SO3 -NAcGlc mimics the sulfated cruzipain epitope that plays a central role in immune recognition.
Cruzipain (Cz), the major cysteine proteinase of Trypanosoma cruzi, is a glycoprotein that contains sulfated high-mannose-type oligosaccharides. We have previously determined that these sulfate groups are targets of specific immune responses. In order to evaluate the structural requirements for antibody recognition of Cz, a systematic structure-activity study of the chemical characteristics needed for antibody binding to the Cz sulfated epitope was performed by immunoassays. With this aim, different synthesized molecules were coupled to the proteins BSA and aprotinin and confronted with (a) mouse sera specific for Cz and its carboxy-terminal (C-T) domain, (b) antibodies raised in rabbits immunized with Cz and its C-terminal domain and (c) IgGs purified from human Chagas disease sera. Our results indicate that a glucosamine containing an esterifying sulfate group in position O-6 and an N-acetyl group was the preferred epitope for the immune recognition of sera specific for Cz and its C-T domain. Although to a minor extent, other anionic compounds bearing sulfate groups in different positions and number as well as different anionic charged groups including carboxylated or phosphorylated monosaccharides, disaccharides and oligosaccharides were recognized. In conclusion, we found that synthetic anionic sugar conjugates containing N-acetyl d-glucosamine-6-sulfate sodium salt (GlcNAc6S) competitively inhibit the binding of affinity purified rabbit anti-C-T IgG to the C-T extension of Cz. Extending these findings to the context of natural infection, immune assays performed with Chagas disease serum confirmed that the structure of synthetic GlcNAc6S mimics the N-glycan-linked sulfated epitope displayed in the C-T domain of Cz.


Characteristic curves for photographic emulsions from nonlinear fitting: a study of statistical and model error.
The intensity calibration of photographic emulsions is examined from the standpoint of nonlinear leastsquares fits to analytic expressions. A simple but widely neglected expression for computing the propagated statistical error is used to examine the error in the relative exposure as determined from the fitted calibration function. The statistical error is also compared with the dependence on the choice of fit function, or model error. In the present applications, which replicate those obtainable routinely in emission spectroscopy, the relative intensity is obtainable to better than 10% over a 2-order-of-magnitude change in intensity.


[A life of Ryu Sang-Kyu, a colonial modernized intellectual].
Many of the Korean intellectuals resisted against suppression of Japanese Imperialism with the people during the Japanese occupation period. Ryu Sang-Kyu was also one of those intellectuals. Ryu Sang-Kyu was born in Gang-gye of North Pyongan-do on 10th November, 1897. He entered Keijo Medical College as one of the first entering students in 1916. However, at the end of his third year, he participated in the 3.1 Independence Movement of Korea and was suspended from the college which was run by the Japanese on account of his participation. Then moving to Shanghai, he joined Heung Sa Dan, an active patriotic group fighting for independence of Korea. He initiated the provisional government of Korea as a network investigator and he played second string to Ahn Chang-Ho, one of major Korean independence activists for four years. In 1923, following Ahn Chang-Ho's advice, he returned to Keijo Medical College to complete the course. Even in colonial Korea, he continued independence movement and was involved in Dong Woo Hoe, the branch of Heung Sa Dan in Korea. After the graduation of Keijo Medical College in 1927, he had served at the department of surgery in Keijo Medical College. In 1930, he participated in founding of the Korean Medical Association. He also raised public awareness by writing to many articles on hygiene and public health issues in public journals and newspapers. In short, he did his best as an intellectual, a medical doctor, an activist of independence movement until he died from streptococcal infection on 7th July, 1936.


Influence of chitosan glutamate on the in vivo intranasal absorption of rokitamycin from microspheres.
Intranasal delivery is an alternative method to target therapeutics to the central nervous system. In the present study, chitosan glutamate (CG)-based mucoadhesive microspheres containing rokitamycin (RK) were prepared by spray-drying and in vitro characterization. Moreover, the influence of CG on RK absorption in bloodstream and cerebrospinal fluid (CSF) was evaluated after nasal administration to rats. The in vivo results were compared with those obtained after nasal administration of chitosan (CH)-based microparticles containing RK and after intravenous (IV) administration of the free drug. The in vitro results indicate that the concentrations of feed solution or kind of CH influence the RK entrapment and size of microspheres. All formulations increase the solubility of this poorly water-soluble drug, but CG is more able to increase the in vitro dissolution rate of RK than CH. CG microspheres absorb water quickly and then dissolve, whereas CH particles need more volume of water for swelling and gelling. In vivo studies showed that, after IV administration, RK is not able to cross the blood-brain barrier and to reach the CSF from the bloodstream. On the contrary, drug goes to the CSF and the bloodstream only after nasal administration of CG microparticles.


An oxidation responsive nano-radiosensitizer increases radiotherapy efficacy by remolding tumor vasculature.
As an excellent candidate material for nano-sensitizers, gold nanostructures have shown great potential in radiotherapy. Nevertheless, severe hypoxia and low accumulation of nanomedicine caused by poor perfusion at the tumor site have significantly reduced radiotherapy efficacy. Vascular normalization has gained attention owing to its ability to relieve hypoxia and increase perfusion. The synergistic therapy of tumor vascular normalization and radiotherapy has become a new option to increase anti-cancer efficacy. However, the commonly used strategy of suppressing a single growth factor to induce vascular normalization is limited by tumor compensatory effects. In this work, we developed a strategy to inhibit oxidative stress in tumors by generating chelating agents in response to hydrogen peroxide, thereby inhibiting multi-angiogenic factors simultaneously to normalize blood vessels. Concretely, sodium alginate (SA) reacted with 8-quinoline boric acid (QBA) to form SA-QBA. Then gold nanoparticles (Au NPs) were modified with SA-QBA to obtain Au@SA-QBA. The system was simple in structure and could generate 8HQ in response to H2O2in vitro to inhibit oxidative stress and reduce the expression of VEGF, bFGF, and Ang-2. In vivo, the perfusion unit (PU) increased by 78% after Au@SA-QBA treatment, and the coverage of pericytes increased by 32%, which in turn induced vascular normalization. In addition, blood routine and blood biochemical tests confirmed its good biocompatibility and 8HQ was not detected in the supernatant after homogenization of major organs. More importantly, after the synergistic treatment of vascular normalization and radiotherapy (4 Gy), the tumor growth inhibition rate was increased by 38.6% compared to the Au@SA-treated group with negligible side effects to normal tissues.


[Primary osteoporosis risk factors in women from Córdoba, Argentina].
Risk factors for osteoporosis were evaluated in women from Cordoba, Argentina. Female patients that consulted about diagnosis or treatment of osteoporosis from January 2000 to June 2002 were included. Secondary osteoporosis patients were excluded. Participants were studied using standardized questionnaire, clinical examination, biochemical analysis, and dual-energy X-ray absorptiometry (DXA). According to lumbar spine DXA results and WHO criterion, we considered 2 groups: Osteoporosis (T score < -2.5 standard deviation, SD) and Control (T score > or = -2.5 SD). One hundred and fifty five women (Osteoporosis Group: 47; 108) were studied. In univariate analysis age, years from menopause, weight, smoking duration, estrogen replacement therapy duration, bilateral oophorectomy with hysterectomy, alkaline phosphatase levels, and Pouteau-Colles fractures were different between both groups. After multivariate analysis, including variables that were statistical different in univariate analysis, and considering osteoporosis as dependent variable, body weight (Odds Ratio, OR=0.92; CI 95% 0.87-0.98), alkaline phosphatase (OR=1.01; CI 95% 1.00-1.02), years from menopause (OR=1.12; CI 95% 1.05-1.21), and Pouteau-Colles fractures (OR=15.15; CI 95% 1.68-135.7) were independent risk factors for osteoporosis.


Genotype Distribution of Panton-Valentine Leukocidin (PVL)-Positive Staphylococcus aureus Strains Isolated from Wound-Related Infections: a Three-Year Multi-Center Study in Tehran, Iran.
The spread of Panton-Valentine leucocidin (PVL)-carrying S. aureus strains in patients with wound infections in both the community and hospitals is increasing in some areas of Iran. In the present study, we determined the molecular characteristics and distribution of PVL-producing S. aureus strains isolated from wound infections. Genes encoding resistance, toxins, and staphylococcal enterotoxins were analyzed by polymerase chain reaction assays. Genotyping was performed using multi-locus sequence typing. Aminoglycoside resistance genes including ant (4')-Ia (57.4%) and aac (6')-Ie/aph (2″) (45.7%) were the most prevalent genes in isolates. Staphylococcal enterotoxin type A, as the most frequent type, was present in 20.2% of isolates. Strains belonged to seven clonal complexes. The most frequent clonal complex was CC30 (ST30) (29.8%), followed by CC22 (ST22) (21.3%), CC8 (ST8 and ST931) (17%), CC88 (ST88) (10.6%), CC59 (ST59 and ST338) (8.5%), CC1 (ST772 and ST1) (7.5%), and CC15 (ST15) (5.3%). Our findings indicated an increasing trend of CC30, carrying a wide range of resistance and toxin genes, which could present an obstacle in the treatment of patients with wound infections. Further studies are required to investigate the carriage of resistance, the antibiotic susceptibility pattern, and toxins encoding genes in different molecular types.


Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders.
Recently, the International Paediatric Multiple Sclerosis Study Group (IPMSSG) definitions for the diagnosis of immune-mediated acquired demyelinating syndromes (ADS) of the central nervous system, including paediatric multiple sclerosis (MS), have been revised. To evaluate the 2012 revised IPMSSG consensus definitions in a cohort of children with ADS prospectively followed from January 2007. Children with ADS who had an MRI scan obtained within 90 days after first disease onset were included. The sensitivity and specificity of the 2007 and 2012 IPMSSG consensus definitions were assessed. The time to MS diagnosis applying the 2007 and 2012 definitions was compared using survival analysis and log-rank test. 82 children with ADS were included. 35 children were diagnosed with paediatric MS, of whom 30 experienced a second clinical event. The final diagnosis corresponded applying either the 2007 or 2012 IPMSSG definitions. The revised 2012 definitions had sufficient sensitivity (80%) and high specificity (100%). MS diagnosis was made 3.4 months earlier (χ(2)=8.24, p=0.004) applying the new definitions. In 14 children, MS diagnosis was made at first MRI. MS diagnosis can be made reliable and early using the 2012 IPMSSG consensus definitions. This is beneficial for adequate counselling of children and their families and for early treatment possibilities.


Sonic fragility of the head-tail bond of bacteriophage P22.
The binding of tail parts to the head of phage P22 is normally irreversible, but after adsorption to host cells sonication releases many of the tail parts intact. This release is dependent on the power of sonication, but is independent of the length of sonication from 2 to 32 s. This phenomenon has been used to show that the upper limit of the number of P22 particles that can bind to a cell is no lower than 700.


A High-Performance Deep Neural Network Model for BI-RADS Classification of Screening Mammography.
Globally, the incidence rate for breast cancer ranks first. Treatment for early-stage breast cancer is highly cost effective. Five-year survival rate for stage 0-2 breast cancer exceeds 90%. Screening mammography has been acknowledged as the most reliable way to diagnose breast cancer at an early stage. Taiwan government has been urging women without any symptoms, aged between 45 and 69, to have a screening mammogram bi-yearly. This brings about a large workload for radiologists. In light of this, this paper presents a deep neural network (DNN)-based model as an efficient and reliable tool to assist radiologists with mammographic interpretation. For the first time in the literature, mammograms are completely classified into BI-RADS categories 0, 1, 2, 3, 4A, 4B, 4C and 5. The proposed model was trained using block-based images segmented from a mammogram dataset of our own. A block-based image was applied to the model as an input, and a BI-RADS category was predicted as an output. At the end of this paper, the outperformance of this work is demonstrated by an overall accuracy of 94.22%, an average sensitivity of 95.31%, an average specificity of 99.15% and an area under curve (AUC) of 0.9723. When applied to breast cancer screening for Asian women who are more likely to have dense breasts, this model is expected to give a higher accuracy than others in the literature, since it was trained using mammograms taken from Taiwanese women.


The potential roles of FGF23 and Klotho in the prognosis of renal and cardiovascular diseases.
Fibroblast growth factor (FGF) 23 and Klotho are two factors associated with several metabolic disorders. Similar to humans, accelerated aging processes characterized by chronic vascular disease, bone demineralization, skin atrophy and emphysema have been recognized in FGF23-null mice and Klotho-deficient mice. The role of these factors in the control of mineral metabolism homeostasis have been shown recently, particularly at the level of parathyroid cells and also in modulating active vitamin D production, two phenomena which are relevant in the presence of chronic kidney disease. In addition, the hormonal affect of circulating FGF23 and Klotho proteins on vascular reactivity, either directly on endothelial cell functions or indirectly by modulating the brain endothelin-1-dependent sympathetic nervous system activity, has contributed to understanding their role in the pathophysiology of hypertension and atherosclerotic vasculopathies. Consequently, very recent clinical investigations seem to confirm the involvement of Klotho in modulating the severity and prognosis of human cardiovascular (CV) disorders and longevity. The present review reports data related to the possible interactive effects of Klotho and FGF23 on the prognosis of renal and CV diseases.


Aggressive Combined Medical and Surgical Management of Mucormycosis Results in Disease Eradication in 2 Pediatric Patients.
Rhinocerebral mucormycosis is an acute, rapidly fatal, fungal infection, classically involving the nasal mucosa and paranasal sinuses. It is an aggressive, opportunistic infection that frequently progresses to involve the orbit and cerebrum. Cerebral extension in immunocompromised patients is almost universally fatal. There are limited data on mucormycosis in pediatric immunocompromised patients in the literature, with only few reports on rhinocerebral involvement. The immunocompromised patients described in this report presented with suspected periorbital and nasal cellulitis, progressing rapidly to necrotic changes in nasal tissue and oral palatal mucosa. In these patients, the surgical resection of mucormycosis-infected tissue followed by flap reconstruction combined with medical treatment effectively treated the infection, allowed for the rapid resumption of chemotherapy and dramatically improved the quality of life for both the patient and their family.


[Pathogenesis of retinal vein occlusions].
Retinal vein occlusion (RVO) is a multifactorial disease and its pathogenesis is still not fully understood. Mechanical, hemodynamic, rheological, coagulation, biochemical, and immunological factors are involved. Two currently prevalent theories of RVO pathogenesis are the mechanical theory and the "coagulopathic" theory. The latter implies an imbalance between thrombogenic factors and antithrombogenic protection. According to some authors, endothelial dysfunction plays a large part in thrombosis development, neoangiogenesis, vascular remodeling, intravascular activation of platelets and leucocytes. In recent studies increasing emphasis is being placed on investigation of immune-mediated mechanisms of vein occlusions. RVO can also be associated with combined hypoxic and free radical tissue damage.


RASCAL is a new human cytomegalovirus-encoded protein that localizes to the nuclear lamina and in cytoplasmic vesicles at late times postinfection.
The products of numerous open reading frames (ORFs) present in the genome of human cytomegalovirus (CMV) have not been characterized. Here, we describe the identification of a new CMV protein localizing to the nuclear envelope and in cytoplasmic vesicles at late times postinfection. Based on this distinctive localization pattern, we called this new protein nuclear rim-associated cytomegaloviral protein, or RASCAL. Two RASCAL isoforms exist, a short version of 97 amino acids encoded by the majority of CMV strains and a longer version of 176 amino acids encoded by the Towne, Toledo, HAN20, and HAN38 strains. Both isoforms colocalize with lamin B in deep intranuclear invaginations of the inner nuclear membrane (INM) and in novel cytoplasmic vesicular structures possibly derived from the nuclear envelope. INM infoldings have been previously described as sites of nucleocapsid egress, which is mediated by the localized disruption of the nuclear lamina, promoted by the activities of viral and cellular kinases recruited by the lamina-associated proteins UL50 and UL53. RASCAL accumulation at the nuclear membrane required the presence of UL50 but not of UL53. RASCAL and UL50 also appeared to specifically interact, suggesting that RASCAL is a new component of the nuclear egress complex (NEC) and possibly involved in mediating nucleocapsid egress from the nucleus. Finally, the presence of RASCAL within cytoplasmic vesicles raises the intriguing possibility that this protein might participate in additional steps of virion maturation occurring after capsid release from the nucleus.


The WHO Tobacco Convention: A New Dawn in the Implementation of International Health Instrument? Comment on "The Legal Strength of International Health Instruments - What It Brings to Global Health Governance?"
The Tobacco Convention was adopted by the World Health Organization (WHO) in 2003. Nikogosian and Kickbusch examine the five potential impacts of the Tobacco Convention and its Protocol on public health. These include the adoption of the Convention would seem to unlock the treaty-making powers of WHO; the impact of the Convention in the global health architecture has been phenomenal globally; the Convention has facilitated the adoption of further instruments to strengthen its implementation at the national level; the Convention has led to the adoption of appropriate legal framework to combat the use of tobacco at the national level and that the impact of the Convention would seem to go beyond public health but has also led to the adoption of the Protocol to Eliminate Illicit Trade in Tobacco. However, the article by Nikogosian and Kickbusch would seem to overlook some of the challenges that may militate against the effective implementation of international law, including the Tobacco Convention, at the national level.


Analysis of Maternal Prenatal Weight and Offspring Cognition and Behavior: Results From the Promotion of Breastfeeding Intervention Trial (PROBIT) Cohort.
Prenatal experiences can influence fetal brain development. To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term. This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records. Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI. Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI. Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points). This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.


Toward economic evaluation of the value of vaccines and other health technologies in addressing AMR.
We discuss the need to make economic evaluations of vaccines antimicrobial resistance (AMR)-sensitive and ways to do so. Such AMR-sensitive evaluations can play a role in value-for-money comparisons of different vaccines within a national immunization program, or in comparisons of vaccine-centric and non-vaccine-centric technologies within an anti-AMR program. In general terms, incremental cost-effectiveness ratios and rates of return and their associated decision rules are unaltered by consideration of AMR-related value. The decision metrics need to have their various health, cost, and socioeconomic terms disaggregated into resistance-related subcategories, which in turn have to be measured carefully before they are reaggregated. The fundamental scientific challenges lie primarily in quantifying the causal impact of health technologies on resistance-related health outcomes, and secondarily in ascertaining the economic value of those outcomes. We emphasize the importance of evaluating vaccines in the context of other potentially complementary and substitutable nonvaccine technologies. Complementarity implies that optimal spending on each set of interventions is positive, and substitutability implies that the ratio of spending will depend on relative value for money. We exemplify this general point through a qualitative discussion of the complementarities and (especially the) substitutability between pneumococcal conjugate vaccines and antimicrobial stewardship and between research and development (R&D) of a gonorrhea vaccine versus R&D of a gonorrhea antibiotic. We propose a roadmap for future work, which includes quantifying the causal effects of vaccination and other health technologies on short-term and long-term resistance-related outcomes, measuring the health-sector costs and broader socioeconomic consequences of resistance-related mortality and morbidity, and evaluating vaccines in the context of nonvaccine complements and substitutes.


Identification of a molecular chaperone in the eukaryotic flagellum and its localization to the site of microtubule assembly.
Monoclonal antibodies that recognize HSP70 family members from evolutionarily divergent organisms were used to identify both constitutively-expressed and stress-inducible HSP70 proteins in the green alga Chlamydomonas. These monoclonal antibodies also cross-reacted with a 70 kDa flagellar protein that comigrated with the constitutively-expressed HSP70 isoform(s) present in the cell body; this is the first identification of a molecular chaperone within the eukaryotic flagellum. Fractionation experiments demonstrated that much of the flagellar HSP70 was bound to the '9+2' microtubule axoneme. Incubation of isolated axonemes in ATP, but not AMP or AMP-PNP, caused significant release of the previously bound HSP70 as is characteristic of complexed HSP70s. Immunofluorescent localization in whole flagella showed that flagellar HSP70 was concentrated at the distal ends of flagella, sites of axonemal assembly in vivo. Extraction of axonemes under ionic conditions known to cause the release of capping structures that link the distal ends of the axonemal microtubules to the flagellar membrane also caused the release of axonemal-bound HSP70. Taken together, these results suggest a model in which an HSP70 chaperone may assist in targeting tubulin and other unassembled axonemal components to the flagellar tip where the chaperone may also participate in the assembly of the '9+2' flagellar axoneme.


Indication for surgical resection in patients with hepatocellular carcinoma with major vascular invasion.
Major portal vein invasion (MVI) by hepatocellular carcinoma (HCC) carries an extremely poor prognosis. Our aim was to clarify the indications of hepatic resection in the presence of MVI by HCC. Between 2001 and 2015, 1,306 patients undergoing primary treatment for HCC were analyzed (866 hepatic resections and 440 transarterial therapies). Significant prognostic factors were identified by retrospectively analyzing tumor status, liver function and treatment. Overall survival was compared in terms of the degree of vascular invasion and treatment. The 5-year survival rates according to the degree of vascular invasion (Vp) were Vp0: 51.9%, Vp1: 33.0%, Vp2: 16.7%, Vp3: 21.8%, and Vp4: 0%, respectively. Overall survival (OS) did not differ significantly between patients with Vp3 and Vp4 MVI (p = 0.153). Median survival following hepatic resection of Vp3 cases was significantly better than that for Vp4 cases (1,913 vs. 258 days, p = 0.014), while OS following transarterial therapy was not significantly different (164 vs. 254 days in Vp3 vs. Vp4, p = 0.137). Multivariate analysis revealed hepatic resection (Odds: 2.335 [95%CI: 1.236-4.718], p = 0.008) and multiple tumors (1.698 [1.029-2.826], p = 0.038) as independent predictors of survival. Hepatic resection in HCC patients with MVI should be indicate in patients with Vp3 invasion.


Ethics and professionalism: what does a resident need to learn?
Training in ethics and professionalism is a fundamental component of residency education, yet there is little empirical information to guide curricula. The objective of this study is to describe empirically derived ethics objectives for ethics and professionalism training for multiple specialties. Study design is a thematic analysis of documents, semi-structured interviews, and focus groups conducted in a setting of an academic medical center, Veterans Administration, and community hospital training more than 1000 residents. Participants were 84 informants in 13 specialties including residents, program directors, faculty, practicing physicians, and ethics committees. Thematic analysis identified commonalities across informants and specialties. Resident and nonresident informants identified consent, interprofessional relationships, family interactions, communication skills, and end-of-life care as essential components of training. Nonresidents also emphasized formal ethics instruction, resource allocation, and self-monitoring, whereas residents emphasized the learning environment and resident-attending interactions. Conclusions are that empirically derived learning needs for ethics and professionalism included many topics, such as informed consent and resource allocation, relevant for most specialties, providing opportunities for shared curricula and resources.


On editing the Journal: Ave atque vale.
Dr. Braceland discusses his 13-year tenure (1965-1978) as Editor of the American Journal of Psychiatry, noting that he took office during a period of social turmoil that in many ways resembled the decade of the Journal's founding 134 years ago. He describes the advantages and disadvantages of the peer review system he introduced to the Journal and states that this approach is essential in a time of ultraspecialization. He reviews the crafts of editing and writing for medical journals, both of which are brightened by clarity and brevity. As to the future of medical journals, he considers reports of their demise premature, while acknowledging the problems they face. Dr. Braceland briefly considered a "rocking chair" approach to his retirement from the Editorship, but the Editor Emeritus will instead continue to provide whatever assistance he can to his colleagues.