Ultrasound focusing using magnetic resonance acoustic radiation force imaging: application to ultrasound transcranial therapy.
Magnetic resonance guided ultrasonic therapy is a promising minimally invasive technology for constantly growing variety of clinical applications. Delivery of focused ultrasound (FUS) energy to the targeted point with optimal intensity is highly desired; however, due to tissue aberrations, optimal focal intensity is not always achieved. Especially in transcranial applications, the acoustic waves are shifted and distorted mainly by the skull. In order to verify that magnetic resonance acoustic radiation force imaging (MR-ARFI) can be used as a focusing tool in transcranial treatments, such an imaging was applied in vivo on a porcine brain via ex vivo human skull. Then, by the use of MR-ARFI technique, an improved ultrasound focusing algorithm is proposed and demonstrated for both transcranial and none brain applications. MR-ARFI images were acquired on a GE 1.5 T scanner equipped with InSightec FUS systems ExAblate 2000 and ExAblate 4000. Imaging was performed with MR-ARFI sequences of line-scan spin-echo and single-shot gradient-echo echo-planar. The in-plane resolution of both acquisitions was 0.9 x 0.9 mm2. The total acquisition time of MR-ARFI image was 31 s by the line-scan sequence and 1 s by the echo-planar sequence. An in vivo experiment was performed using FUS transducer, which is built out of 1024 ultrasound transmitting piezoelectric elements at 220 kHz frequency. The transducer was focused into the brain of a pig, which was wrapped in a human skull, in degassed water environment to resemble human treatments. The pig underwent a wide bilateral craniectomy to prevent a bone heating from the ultrasound beams. Two focusing experiments were performed in phantoms using 1 MHz and 710 kHz FUS transducers working with 208 and 225 elements, respectively. In the first experiment, aberration was added virtually to the apparatus by adding random phases to the phase map of the transducer. A simple focusing correction scheme was used, in which the corrected phase of a group of elements was chosen such that it maximizes the radiation force at the focal point. In the second experiment, aberrations made by a human skull were corrected using geometrical and phase based adjustments on segments of the transducer. A maximum displacement of 10 microm was obtained using 1.4 kW acoustic power on a live pig's head that its skull was removed and replaced by ex vivo human skull. Aberration correction using MR-ARFI resulted in near optimal focus, as the radiation force was similar to the nonaberration case. Transcranial, MR-ARFI based aberration correction performed better than CT based aberration correction, a technique that is currently used in brain FUS treatments. In the present work, the authors show for the first time a result of MR-ARFI in a live brain through ex vivo human skull. They have demonstrated that aberration correction could be done using MR-ARFI by measuring the radiation force at the focal point. Aberration correction using MR-ARFI is a promising noninvasive technique for transcranial focusing, which may result in near optimal focus and more reliable and safer brain FUS treatments.


Delaying second births among adolescent mothers: a randomized, controlled trial of a home-based mentoring program.
Rates of rapid second births among low-income black adolescent mothers range from 20% to 50%. Most efforts to prevent rapid second births have been unsuccessful. There were 4 objectives: (1) to examine whether a home-based mentoring intervention was effective in preventing second births within 2 years of the adolescent mother's first delivery; (2) to examine whether greater intervention participation increased the likelihood of preventing a second birth; (3) to examine whether second births were better predicted from a risk practice perspective or a family formation perspective, based on information collected at delivery; and (4) to examine how risk practices or family formation over the first 2 years of parenthood were related to a second birth. We conducted a randomized, controlled trial of a home-based intervention curriculum, based on social cognitive theory, and focused on interpersonal negotiation skills, adolescent development, and parenting. The curriculum was delivered biweekly until the infant's first birthday by college-educated, black, single mothers who served as mentors, presenting themselves as "big sisters." The control group received usual care. Follow-up evaluations were conducted in the homes 6, 13, and 24 months after recruitment. Participants were recruited from urban hospitals at delivery and were 181 first time, black adolescent mothers (< 18 years of age); 82% (149 of 181) completed the 24-month evaluation. Intent-to-treat analyses revealed that control mothers were more likely than intervention mothers to have a second infant. The complier average causal effect was used to account for variability in intervention participation. Having > or = 2 intervention visits increased the odds of not having a second infant more than threefold. Only 1 mother who completed > or = 6 visits had a second infant. At delivery of their first infant, mothers who had a second infant were slightly older (16.7 vs 16.2 years) and were more likely to have been arrested (30% vs 14%). There were no differences in baseline contraceptive use or other measures of risk or family formation. At 24 months, mothers who had a second infant reported high self-esteem, positive life events, and romantic involvement and residence with the first infant's father. At 24 months, there were no differences in marital rates (2%), risk practices, or contraceptive use between mothers who did and did not have a second infant. Mothers who did not have a second infant were marginally more likely to report no plans for contraception in their next sexual contact compared with mothers who had a second infant (22% vs 8%, respectively). A home-based intervention founded on a mentorship model and targeted toward adolescent development, including negotiation skills, was effective in preventing rapid repeat births among low-income, black adolescent mothers. The effectiveness of the intervention could be seen after only 2 visits and increased over time. There were no second births among mothers who attended > or = 8 sessions. There was no evidence that risk behavior or contraceptive use was related to rapid second births. There was some evidence that rapid second births among adolescent mothers were regarded as desirable and as part of a move toward increasing autonomy and family formation, thereby undermining intervention programs that focus on risk avoidance. Findings suggest the merits of a mentoring program for low-income, black adolescent mothers, based on a relatively brief (6-8 sessions) curriculum targeted toward adolescent development and interpersonal negotiation skills.


Comparing apical preparations of root canals shaped by nickel-titanium rotary instruments and nickel-titanium hand instruments.
This study measured displacement of canal centers in extracted human teeth after preparation by Lightspeed and nickel-titanium K-files. The specimens were divided into two groups (n = 11), after radiographing the roots from the buccolingual and mesiodistal planes with pathfinding files in situ. More strongly and less strongly curved canals were, respectively, assigned to the Lightspeed and nickel-titanium K-file groups. Using a reassembly technique, cross-sections at 1.25 mm, 3.25 mm, and 5.25 mm from the apices were made of the experimental roots embedded in clear plastic. Stereomicroscopic 35-mm slides were taken of the uninstrumented sectioned canals. The sections were reassembled and then prepared to size 50 Master Apical Rotary and size 40 Master Apical Files, for the Lightspeed and K-file groups, respectively. Similar 35-mm slides of the instrumented canals were taken and electronically superimposed over their uninstrumented counterparts. Displacements of root canal centers after preparation and increases in cross-sectional areas of the prepared root canals were evaluated at specific levels. No significant differences in displacement of canal centers or between the mean cross-sectional areas of the instrumented root canals were recorded between the Lightspeed and K-file groups. Both types of instruments produced similar displacement of canal centers after preparation.


Integrated inference and evaluation of host-fungi interaction networks.
Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host-pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host-fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen-host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi-human and fungi-mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host-fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host-fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host-fungi transcriptome and proteome data.


Surgical approach to neonatal intestinal perforation. An analysis on 85 cases (1991-2001).
Primary gastrointestinal perforations have an incidence of between 1% and 3% in NICU patients. The 3 Centers participating in this study cover nearly 40% of the NICU population of the Lazio Region--Italy. The aim of this study is to discuss factors affecting survival in patients affected by a primary intestinal perforation. From 1991 to 2001, 67 cases of 85 with a neonatal gastrointestinal perforation, were related to primary bowel lesions. Necrotizing enterocolitis (NEC) was not always the cause of perforation and in many patients an isolated bowel lesion without signs of NEC was found. The aim of this study was to examine clinical and intraoperative findings of NEC and non NEC perforations and their impact on survival. A relevant number of these patients were extremely low-birth weight (ELBW). Controversies about treatment of this category of neonates are discussed. Patients were 37 males and 30 females (mean birth weight 1 274.8 g, mean gestational age 28.9 weeks, mean age at perforation 10 days). Overall survival was 56.8%. Patients were divided by intraoperative findings in 2 groups: NEC (n=48), or isolated intestinal perforation (IIP) without signs of NEC (n=19). Differences between these 2 groups with regard to birth weight, maturity, associated cardiac anomalies (patent ductus arteriosus, PDA) were significant. NEC and IIP behaved as 2 distinct entities, each with peculiar clinical (age at perforation, oral feeding, need of ventilatory support) and radiological aspects. At surgery, multiple lesion on necrotic bowel were typical of NEC versus single, isolated perforations on healthy bowel typical of IIP. Overall survival was almost identical in the 2 groups (59% vs 58%). ELBW patients (55% of the total neonatal intestinal perforations) were also studied. There were 21 patients with NEC and 16 with IIP. The 2 groups were different in age at perforation, previous oral feeding and associated cardiac anomalies (PDA). Overall survival was 62% for NEC and 50% for IIP. A laparotomy was always performed. Temporary peritoneal drainage was done in 4 cases only. Results were better when intestinal diversion was performed rather than resection and primary anastomosis. Almost all NEC patients had multiple perforations and extended bowel necrosis. NEC is the most frequent cause of neonatal intestinal perforation. This is a quite distinct entity from IIP, which must always be differentiated preoperatively and which is most frequently found among low birth weight newborns. As far as surgical treatment of perforation among ELBW neonates is concerned, peritoneal drainage might be reasonably performed when a single lesion on healthy bowel as in IIP is clearly diagnosed but it could be inadequate for NEC patients.


Pathogen burden and cortisol profiles over the day.
Hypothalamic-pituitary-adrenocortical (HPA) regulation in adults is influenced by early psychosocial adversity, but the role of infectious disease history is poorly understood. We studied the association between cumulative pathogen burden and cortisol profile over the day in a sample of 317 healthy men and women aged 51-72 years. Cumulative pathogen burden was defined as positive serostatus for Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1). Salivary cortisol was sampled repeatedly over the day. The cortisol slope was defined as the decrease across the day and evening. Age, gender, grade of employment, body mass index, smoking status, self-rated health, cardiovascular medication, depressed mood and time of waking were included as covariates. The pathogen burden averaged 1.76 (s.d.=0.92). The cortisol slope was inversely associated with pathogen burden after controlling for covariates. When individual pathogens were studied, only CMV was associated with flatter cortisol rhythms in isolation. We conclude that pathogen burden is independently associated with flatter cortisol slopes over the day, and may contribute to disturbed neuroendocrine regulation.


Home blood pressure monitoring in the 21st century.
Home blood pressure monitoring provides multiple measurements in the usual environment of each individual, allows the detection of intermediate hypertension phenotypes (white-coat and masked hypertension), and appears to have superior prognostic value compared to the conventional office blood pressure measurements. Accumulating evidence suggests that home blood pressure monitoring improves long-term hypertension control rates. Moreover, it is widely available, relatively inexpensive, and well accepted by patients. Thus, current guidelines recommend home blood pressure monitoring as an essential method for the evaluation of almost all untreated and treated patients with suspected or treated hypertension. Validated automated upper-arm cuff devices with automated storage and averaging of readings should be used. The home blood pressure monitoring schedule for 4 to 7 days with exclusion of the first day (12-24 readings) should be averaged to provide values for decision making.


Prevalence of Entamoeba histolytica, Giardia lamblia, and Cryptosporidium spp. in Libya: 2000-2015.
The intestinal protozoa Entamoeba histolytica, Giardia lamblia, and Cryptosporidium spp. are the causative agents of giardiasis, amebiasis, and cryptosporidiosis, respectively. Adequate knowledge of the geographical distribution of parasites and the demographic variables that influence their prevalence is important for effective control of infection in at-risk populations. The data were obtained by an English language literature search of Medline and PubMed for papers using the search terms 'intestinal parasites and Libya, G. lamblia and Libya, E. histolytica and Libya and Cryptosporidium and Libya' for the period 2000-2015. The data obtained for the period 2000-2015 showed prevalence rates of 0.8-36.6% (mean 19.9%) for E. histolytica/dispar, 1.2-18.2% (mean 4.6%) for G. lamblia and 0.9-13% (mean 3.4%) for Cryptosporidium spp. among individuals in Libya with gastroenteritis (GE). On the other hand, prevalence rates of 0.8-16.3% (mean 8.3%), 1.8-28.8% (mean 4.8%), and 1.0-2.5% (mean=2.4), respectively, were observed for individuals without GE. The mean prevalence rate of E. histolytica/dispar was significantly higher among individuals with GE compared with those without GE (p<0.0000001, OR=2.74). No significant difference in prevalence rate of the three organisms was found according to gender, but most of infections were observed in children aged 10 years or younger. The reviewed data suggest that E. histolytica, G. lamblia, and Cryptosporidium spp. may play a minor role in GE in Libya. The observed high prevalence rates of E. histolytica/dispar reported from Libya could be due mainly to the non-pathogenic E. dispar and E. moshkovskii. However, more studies are needed in the future using E. histolytica-specific enzyme immunoassays and/or molecular methods to confirm this observation.


Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease.
Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the third found only in North African Jews with GSD-IIIa. Here we report two frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. A novel point mutation of a single T deletion at cDNA position 3964 (3964delT) was first detected in an African American patient, who has a severe phenotype and early onset of clinical symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, previously implicated as a IIIb mutation in a Japanese patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the molecular defects in the GSD-III patients tested. Our molecular and clinical data suggest a genotype-phenotype correlation for each of these mutations. Furthermore, this current study, coupled with our previous reports, describes the molecular tools necessary for the development of a DNA-based diagnostic test for GSD-III.


Genotypic difference in salinity tolerance in quinoa is determined by differential control of xylem Na(+) loading and stomatal density.
Quinoa is regarded as a highly salt tolerant halophyte crop, of great potential for cultivation on saline areas around the world. Fourteen quinoa genotypes of different geographical origin, differing in salinity tolerance, were grown under greenhouse conditions. Salinity treatment started on 10 day old seedlings. Six weeks after the treatment commenced, leaf sap Na and K content and osmolality, stomatal density, chlorophyll fluorescence characteristics, and xylem sap Na and K composition were measured. Responses to salinity differed greatly among the varieties. All cultivars had substantially increased K(+) concentrations in the leaf sap, but the most tolerant cultivars had lower xylem Na(+) content at the time of sampling. Most tolerant cultivars had lowest leaf sap osmolality. All varieties reduced stomata density when grown under saline conditions. All varieties clustered into two groups (includers and excluders) depending on their strategy of handling Na(+) under saline conditions. Under control (non-saline) conditions, a strong positive correlation was observed between salinity tolerance and plants ability to accumulate Na(+) in the shoot. Increased leaf sap K(+), controlled Na(+) loading to the xylem, and reduced stomata density are important physiological traits contributing to genotypic differences in salinity tolerance in quinoa, a halophyte species from Chenopodium family.


Adult T-cell leukemia/lymphoma and HTLV-1.
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus to be discovered, more than 25 years ago. HTLV-1 infects 15 to 20 million individuals worldwide. This oncoretrovirus can be transmitted in three ways: horizontally (sexually), vertically (mother to child), and via blood transfusion. HTLV-1 causes two major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). ATLL can be classified into four major subtypes: a smoldering type, a chronic type, a lymphoma type, and a leukemic type. Because of intrinsic chemoresistance and severe immunosuppression, the survival rate of ATLL patients, especially those who develop the acute leukemic or lymphoma forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations. This article discusses a number of recent treatments including antiretroviral therapy, aggressive chemotherapy, and allogeneic bone-marrow transplantation, as well as new drugs.


The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53.
The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, all A3 genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of most A3 genes (including A3C and A3H) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 stabilizer Nutlin led to repression of the A3B gene. Furthermore, p53 could enhance IFN type-I induction of A3 genes. Interestingly, overexpression of a group of tumor-associated p53 mutants in TP53-null cancer cells promoted A3B expression. These findings establish that the "guardian of the genome" role ascribed to p53 also extends to a unique component of the immune system, the A3 genes, thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis.Implications: Activated p53 can integrate chromosomal stresses and immune responses through its influence on expression of APOBEC3 genes, which are key components of the innate immune system that also influence genomic stability. Mol Cancer Res; 15(6); 735-44. ©2017 AACR.


Conflict management in public hospitals: the Cyprus case.
Conflict among health-care personnel has been identified as an issue within health-care settings around the world. To investigate the existence and management of conflict among health-care personnel in public hospitals in Cyprus; to assess the factors leading to conflict among staff members; to evaluate the consequences of conflict arising; and to consider the management strategies. A self-administered questionnaire was completed by a random sample of 1037 health-care professionals in all (seven) state-run hospitals in Cyprus in 2008. Mean age of respondents was 41 years, and 75% were female. Sixty-four per cent of respondents reported that they had never been informed about conflict management strategies, with physicians being the least informed as the relative percentage was 79.8% (χ(2) = 33, P < 0.001). Sixty per cent of health-care professionals reported conflict at work with other health-care personnel one to five times per week, and 37% of the respondents stated that they devote 90 min (mean value) from work during their shift in conflict resolution, meaning that managing conflicts may absorb 19% of working time daily. The majority of respondents agreed that organizational problems and communication gaps were the main issues creating conflict. Avoidance and collaboration were the preferable strategies for conflict resolution, used by 36.6% and 37.5% of the respondents, respectively. Better communication, fair management practices and clear job descriptions and expectations may be needed in order to facilitate change and reverse the negative atmosphere that exists. Further education in conflict management for physicians, nurses and their managers may also be needed.


A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast.
The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women (P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital (n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women (P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast.


Prospective Analysis of Health and Mortality Risk in Veteran and Non-Veteran Participants in the Women's Health Initiative.
The health of postmenopausal women veterans is a neglected area of study. A stronger empirical evidence base is needed, and would inform the provision of health care for the nearly 1 million U.S. women veterans currently 50 years of age or older. To this end, the present work compares salient health outcomes and risk of all-cause mortality among veteran and non-veteran participants of the Women's Health Initiative (WHI). This study features prospective analysis of long-term health outcomes and mortality risk (average follow-up, 8 years) among the 3,706 women veterans and 141,009 non-veterans who participated in the WHI Observational Study or Clinical Trials. Outcome measurements included confirmed incident cases of cardiovascular disease (CVD), cancer, diabetes, hip fractures, and all-cause mortality. We identified 17,968 cases of CVD, 19,152 cases of cancer, 18,718 cases of diabetes, 2,817 cases of hip fracture, and 13,747 deaths. In Cox regression models adjusted for age, sociodemographic variables, and health risk factors, veteran status was associated with significantly increased risk of all-cause mortality (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23), but not with risk of CVD (HR, 1.00; 95% CI, 0.90-1.11), cancer (HR, 1.04; 95% CI, 0.95-1.14), hip fracture (HR, 1.16; 95% CI, 0.94-1.43), or diabetes (HR, 1.00; 95% CI, 0.89-1.1). Women veterans' postmenopausal health, particularly risk for all-cause mortality, warrants further consideration. In particular, efforts to identify and address modifiable risk factors associated with all-cause mortality are needed.


Oral mucosal screening and referral attitudes of Australian oral health therapists and dental hygienists in Queensland.
The aim of this study was to describe oral mucosal screening and referral attitudes of Australian oral health therapists (OHTs) and dental hygienists (DHs). Questionnaires were distributed to participants who attended dental hygiene courses run in both regional and metropolitan Queensland. One hundred and two participants comprised 58 OHTs and 44 DHs, with a mean of 8.9 years since graduation. Thirty-four participants worked in regional locations, while 68 were from metropolitan areas. 97% of participants agreed that mucosal screening should be performed for all new and recall patients, while a minority (5%) agreed that patients will detect an oral mucosal change themselves. The majority (77%) agreed that oral cancer would be encountered in their practising career. Most participants (81%) felt comfortable discussing the presence of a suspicious lesion with patients and 88% agreed that it was their role to screen. In terms of barriers to oral cancer screening, lack of training was seen as the most prevalent barrier (56%) followed by lack of confidence (51%). Lack of time was seen as the third most prevalent barrier (40%), and lack of financial incentives was the least prevalent barrier (16%). Oral health therapists and DHs understand the importance of oral mucosal screening and are likely to be alert to oral mucosal changes. While lack of time and financial incentives was perceived to be impediments to mucosal screening, lack of confidence and training was the most prevalent barriers. This issue should be addressed through implementation of effective continuing education courses targeting oral cancer screening and referral practices.


A review of the Ponseti method and development of an infant clubfoot program in Vietnam.
The Feet for Walking clubfoot project from Australia formally introduced the Ponseti technique in Vietnam in 2004 and is based at the Da Nang Orthopedic and Rehabilitation Centre in central Vietnam. We provide an initial overview of the management of infant clubfoot deformity using the nonsurgical Ponseti method. Early indicators of the outcome of implementing this clubfoot project are largely positive but also require ongoing review. Further analyses of the use of the Ponseti method (or obstacles preventing the same) following training of personnel is underway. Recent research has improved and refined the technique that must now be both appreciated and incorporated by clinicians. This technique is used across the world in both developed and developing countries and is universally regarded as the best management method for clubfoot deformities.


In silico identification of bacteriocin gene clusters in the gastrointestinal tract, based on the Human Microbiome Project's reference genome database.
The human gut microbiota comprises approximately 100 trillion microbial cells which significantly impact many aspects of human physiology - including metabolism, nutrient absorption and immune function. Disturbances in this population have been implicated in many conditions and diseases, including obesity, type-2 diabetes and inflammatory bowel disease. This suggests that targeted manipulation or shaping of the gut microbiota, by bacteriocins and other antimicrobials, has potential as a therapeutic tool for the prevention or treatment of these conditions. With this in mind, several studies have used traditional culture-dependent approaches to successfully identify bacteriocin-producers from the mammalian gut. In silico-based approaches to identify novel gene clusters are now also being utilised to take advantage of the vast amount of data currently being generated by next generation sequencing technologies. In this study, we employed an in silico screening approach to mine potential bacteriocin clusters in genome-sequenced isolates from the gastrointestinal tract (GIT). More specifically, the bacteriocin genome-mining tool BAGEL3 was used to identify potential bacteriocin producers in the genomes of the GIT subset of the Human Microbiome Project's reference genome database. Each of the identified gene clusters were manually annotated and potential bacteriocin-associated genes were evaluated. We identified 74 clusters of note from 59 unique members of the Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria and Synergistetes. The most commonly identified class of bacteriocin was the >10 kDa class, formerly known as bacteriolysins, followed by lantibiotics and sactipeptides. Multiple bacteriocin gene clusters were identified in a dataset representative of the human gut microbiota. Interestingly, many of these were associated with species and genera which are not typically associated with bacteriocin production.


Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides.
Nucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on this prototype compound. These include substitution of the ethoxy group at the C-4″ position by alkoxy groups of different length, branching, conformational freedom or functionalization. In addition, the 4″-ethoxy group has been removed or substituted by other functional groups. The role of the tert-butyldimethylsilyl (TBDMS) group at the 2' position has also been studied by preparing the corresponding 2'-deprotected derivative or by replacing it by other silyl (tert-hexyldimethylsilyl) or acyl (acetyl) moieties. Finally, the thymine of the prototype compound has been replaced by N-3-methylthymine, uracil or thiophenyl. Some of these compounds were endowed with a 6- to 7-fold higher selectivity than the prototype 1. The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase.


Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.
The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.


Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study.
Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. A multicentre, international, collaborative cohort study. 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. All-cause mortality at 30 days and 90 days. 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.


A Competing Nomogram to Predict Survival Outcomes in Invasive Micropapillary Breast Cancer.
Background: Although it is widely accepted that invasive micropapillary carcinoma (IMPC) presents more aggressive behavior and has a higher aggressive behavior, the prognosis of IMPC compared with invasive ductal carcinoma (IDC) remains controversial. We conducted this study to explore gene expression profiles of IMPC and establish a competing nomogram that predicts the survival outcomes across these two groups of patients. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed. Propensity score matching (PSM) was used to adjust for potential baseline confounding between IMPC and IDC group. The Kaplan-Meier method was used to calculate the occurrence of overall mortality. The Gray method was used to estimate the rate of breast cancer specific death (BCSD). A competing regression model was used to evaluate factors associated with BCSD. A nomogram based on the competing risk regression model was established to predict individual outcomes. IMPC-specific gene expression profiles were explored using microarrays data from the Gene Expression Omnibus (GEO) database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed. Results: In this study, 330786 (99.62%) patients with IDC 1247 (0.38%) patients with IMPC were included. Patients with IMPC had more lymph node involvement and a larger tumor size compared with those with IDC. After PSM, many distributional differences were eliminated, showing that the IMPC and IDC group were more similar. Patients with IMPC had a favorable prognosis with statistical significance compared with patients with IDC (overall mortality HR = 0.68; 95%CI, 0.53-0.86; P = 0.002). Based on Gray method, patients with IMPC had a favorable prognosis with significant statistical significance compared with patients with IDC (BCSD SHR = 0.64; 95%CI, 0.47-0.88; P = 0.006). Multivariate analysis based on competing risk model demonstrated that IMPC was a favorable independent factor for BCSD. The nomogram could accurately predict BCSD with a high internal and external validated C-index (0.835, 0.818 respectively). A total of 53 upregulated differentially expressed genes (DEGs) and 40 downregulated DEGs of IMPC was identified. The GO analysis results showed that downregulated DEGs were significantly enriched in extracellular structure organization, extracellular matrix, cell-substrate adhesion junction. KEGG analysis of selective gene sets shows that downregulated DEGs significantly enriched for processes related to carbon metabolism, Rap1 signaling pathway. Conclusion: In the current study, IMPC accounted for 0.38% of the entire cohort. IMPC was found to be a favorable independent prognostic factor. The present study identified gene expression profiles and signal pathways of IMPC. The developed nomogram can help the oncologists to predict individual outcomes more accurately.


In-hospital worsening heart failure.
Acute worsening heart failure (WHF) is seen in a sizable portion of patients hospitalized for heart failure, and is increasingly being recognized as an entity that is associated with an adverse in-hospital course. WHF is generally defined as worsening heart failure symptoms and signs requiring an intensification of therapy, and is reported to be seen in anywhere from 5% to 42% of heart failure admissions. It is difficult to ascertain the exact epidemiology of WHF due to varying definitions used in the literature. Studies indicate that WHF cannot be precisely predicted on the basis of baseline variables assessed at the time of admission. Recent data suggest that some experimental therapies may reduce the risk of development of WHF among hospitalized heart failure patients, and this is associated with a reduction in risk of subsequent post-discharge cardiovascular mortality. In this respect, WHF holds promise as a endpoint for acute heart failure clinical trials to better elucidate the benefit of targeted novel therapies. Better understanding of the pathophysiology and a consensus on the definition of WHF will further improve our epidemiological and clinical understanding of this entity.


Permeability criteria for effective function of passive countercurrent multiplier.
The urine concentrating effect of the mammalian renal inner medulla has been attributed to countercurrent multiplication of a transepithelial osmotic difference arising from passive absorption of NaCl from thin ascending limbs of long loops of Henle. This study assesses, both mathematically and experimentally, whether the permeability criteria for effective function of this passive hypothesis are consistent with transport properties measured in long loops of Henle of chinchilla. Mathematical simulations incorporating loop of Henle transepithelial permeabilities idealized for the passive hypothesis generated a steep inner medullary osmotic gradient, confirming the fundamental feasibility of the passive hypothesis. However, when permeabilities measured in chinchilla were used, no inner medullary gradient was generated. A key parameter in the apparent failure of the passive hypothesis is the long-loop descending limb (LDL) urea permeability, which must be small to prevent significant transepithelial urea flux into inner medullary LDL. Consequently, experiments in isolated perfused thin LDL were conducted to determine whether the urea permeability may be lower under conditions more nearly resembling those in the inner medulla. LDL segments were dissected from 30-70% of the distance along the inner medullary axis of the chinchilla kidney. The factors tested were NaCl concentration (125-400 mM in perfusate and bath), urea concentration (5-500 mM in perfusate and bath), calcium concentration (2-8 mM in perfusate and bath), and protamine concentration (300 micrograms/ml in perfusate). None of these factors significantly altered the measured urea permeability, which exceeded 20 x 10(-5) cm/s for all conditions. Simulation results show that this moderately high urea permeability in LDL is an order of magnitude too high for effective operation of the passive countercurrent multiplier.


Effects of Low-Level Laser Therapy in Autism Spectrum Disorder.
The study examined the efficacy of low-level laser therapy, a form of photobiomodulation, for the treatment of irritability associated with autistic spectrum disorder in children and adolescents aged 5-17 years. Twenty-one of the 40 participants received eight 5-min procedures administered to the base of the skull and temporal areas across a 4-week period (test, i.e., active treatment participants). All the participants were evaluated with the Aberrant Behavior Checklist (ABC), with the global scale and five subscales (irritability/agitation, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech), and the Clinical Global Impressions (CGI) Scale including a severity-of-illness scale (CGI-S) and a global improvement/change scale (CGI-C). The evaluation took place at baseline, week 2 (interim), week 4 (endpoint), and week 8 (post-procedure) of the study. The adjusted mean difference in the baseline to study endpoint change in the ABC irritability subscale score between test and placebo participants was -15.17 in favor of the test procedure group. ANCOVA analysis found this difference to be statistically significant (F = 99.34, p < 0.0001) compared to the baseline ABC irritability subscale score. The study found that low-level laser therapy could be an effective tool for reducing irritability and other symptoms and behaviors associated with the autistic spectrum disorder in children and adolescents, with positive changes maintained and augmented over time.


Ethical challenges in transplant practice in Latin America: the Aguascalientes Document.
Organ transplants are currently an alternative treatment for a growing number of diseases, which were previously considered terminal. Bioethics has played an important role since the advent of this surgical technique, mainly in defining death criteria and the optimum transplantation conditions. This issue continues being a universal focal point, mainly concerning the equity of access to transplantation, criteria for assigning deceased-donor organs, living-donor safety, risk of commercial trade, fair access to high-quality immunosuppressive drugs and organ transplant legislation. These problems are characteristic of Latin America and the Caribbean, and were the driving force behind the First Latin American Bioethics and Transplant Forum, sponsored by the Latin American and Caribbean Transplant Society (STALYC), and all the transplant societies from subsidiary countries. The "Document of Aguascalientes" is a collection of all the ideas and opinions that were proposed during round tables and analyses. The document is divided into four sections: 1) living donor; 2) organ trading and transplant tourism; 3) the state role in legislation, transplant distribution and coverage; and 4) access to and quality of immunosuppression. The Bioethics and Transplant Forum was created to analyse and find solutions for this complex issue. The "Document of Aguascalientes" aims to serve as an instrument of expression and a vehicle for the ideas put forward during the Forum, so that they can act as transplant practice guidelines in Latin America.


Ultrastructural studies of the dying-back process. VI. Examination of nerve fibers undergoing giant axonal degeneration in organotypic culture.
Organotypic tissue cultures, composed of structurally and functionally coupled explants of mouse spinal cord, dorsal root ganglia, and striated muscle, have been used to create a model of the distal (dying-back) axonopathy found in animals and humans with aliphatic hexacarbon neuropathy. Mature explants were treated with 50-650 micrograms/ml of the following hexacarbons dissolved in nutrient fluid: n-hexane, 2-hexanol, 2,5-hexanediol, methyl n-butyl ketone, 5-hydroxy-2-hexanone, 2,5-hexanedione (all neurotoxic), or 2,4-hexanedione (a non-neurotoxic diketone). High concentrations (400-650 micrograms/ml) induced pancytotoxic damage and necrosis of tissue within days, while the lower doses (50-100 micrograms/ml) induced no pathological changes over a period of several weeks. Continuous exposure of explants to 245-325 micrograms/ml (2.8 mM) of the neurotoxic hexacarbons caused specific pathological changes to develop in distal nerve fibers after three to six weeks. Initial changes seen in distal, nonterminal regions of myelinated fibers included: nodal elongation, axonal swellings on proximal-side paranodes, and paranodal myelin retraction. Prolonged treatment was associated with Wallerian-like degeneration of distal nerve fibers. Denuded paranodal swellings in more proximal regions of affected myelinated fibers adopted a more-normal size and underwent remyelination; this occurred during and after the course of treatment. Remyelination by lateral extension from adjacent Schwann cells was documented in living and fixed tissue. The observations confirm the spatial-temporal evolution of hexacarbon distal axonopathy previously suggested from comparable studies in vivo.


Complexity Assessment and Monitoring to Ensure Optimal Outcomes Tool for Measuring Pediatric Critical Care Nursing.
Historically, nursing productivity has been measured in adult settings and based on time, intensity, and resource allocation. To develop a comprehensive measure of pediatric critical care nursing workload. An expert panel of pediatric critical care nurses used a modified Delphi method to identify 14 domains of nursing care with a number of corresponding care items in each domain. By consensus, they assigned each care item a cognitive complexity rating from 1 to 5. The panel next developed a classification system (classes I-V) to support interpretation of the patient's total score. The Complexity Assessment and Monitoring to Ensure Optimal Outcomes (CAMEO) tool was initiated with a cohort of 75 pediatric cardiac critical care patients to verify comprehensive capture of nursing care. Results of completed CAMEO tools were summarized by using descriptive statistics. The cognitive workload across 14 domains of care was described, and each care item in the domain was scored. The range of CAMEO total scores was 25 to 230 (median, 124). For the initial cohort of patients, the cognitive complexity of care classifications were 13% as class I or II, 80% as class III or IV, and 7% as class V. The CAMEO tool was comprehensive in describing and quantifying the cognitive workload of pediatric critical care nurses. The CAMEO classification process informs staffing needs that support synergy between the needs of patients and their families and nurses' knowledge and skill. Articulation of nursing care focused on informed clinical decision making is needed to justify the value of skilled nurses.


Guideline for the diagnosis and management of multiple sclerosis in children.
Paediatric multiple sclerosis (MS) represents a particular MS subgroup with unique diagnostic challenges. Due to the narrow window of environmental exposures and clinical disease expression, children with MS may represent an important study population for gaining a better understanding of the pathogenesis of the disease. The International Paediatric MS Study Group (IPMSSG) was formulated to clarify the diagnostic and therapeutic dilemmas in this population. This guideline was adapted from the International Paediatric Multiple Sclerosis Study Group guideline and endorsed by PANDA, South Africa.


The Chemical Characteristics and Immune-Modulating Activity of Polysaccharides Isolated from Cold-Brew Coffee.
To elucidate new biological ingredients in cold-brew coffee extracted with cold water, crude polysaccharide (CCP-0) was isolated by ethanol precipitation, and its immune-stimulating activities were assayed. CCP-0 mainly comprised galactose (53.6%), mannose (15.7%), arabinose (11.9%), and uronic acid (12.4%), suggesting that it might exist as a mixture of galactomannan and arabinogalactan. CCP-0 significantly increased cell proliferation on both murine peritoneal macrophages and splenocytes in a dose dependent manner. CCP-0 also significantly augmented nitric oxide and reactive oxygen species production by murine peritoneal macrophages. In addition, macrophages stimulated by CCP-0 enhanced production of various cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and IL-12. In an in vitro assay for intestinal immune-modulating activity, CCP-0 showed higher bone-marrow cell-proliferation activity through Peyer's patch cells at 100 μg/mL than the negative control. These results suggest that CCP-0 may potentially enhance macrophage functions and the intestinal immune system.


Cell Systems to Investigate the Impact of Polyphenols on Cardiovascular Health.
Polyphenols are a diverse group of micronutrients from plant origin that may serve as antioxidants and that contribute to human health in general. More specifically, many research groups have investigated their protective effect against cardiovascular diseases in several animal studies and human trials. Yet, because of the excessive processing of the polyphenol structure by human cells and the residing intestinal microbial community, which results in a large variability between the test subjects, the exact mechanisms of their protective effects are still under investigation. To this end, simplified cell culture systems have been used to decrease the inter-individual variability in mechanistic studies. In this review, we will discuss the different cell culture models that have been used so far for polyphenol research in the context of cardiovascular diseases. We will also review the current trends in cell culture research, including co-culture methodologies. Finally, we will discuss the potential of these advanced models to screen for cardiovascular effects of the large pool of bioactive polyphenols present in foods and their metabolites.


Potential impact of a targeted cardiopulmonary resuscitation program for older adults on survival from private-residence cardiac arrest.
Traditional cardiopulmonary resuscitation (CPR) training programs do not target older adults who are most likely to witness private-residence cardiac arrests and do not reliably result in a bystander who is likely to perform CPR in the event of an arrest. This study was performed to compare targeted CPR training programs for older adults (older than 50 years) that 1) increase numbers of CPR-trained bystanders of private-residence cardiac arrest or 2) increase the percentage of trained bystanders of private-residence cardiac arrest who perform CPR. A simultaneous outcome was to estimate the minimal significant survival benefit associated with each of the training programs. A probabilistic simulation model was developed in Fortran95 that incorporated key out-of-hospital cardiac arrest elements, including witnessed arrests, CPR-trained witness, CPR provision, and impact of CPR on ventricular fibrillation. Input data were derived from published or publicly available data, including a large prospective cohort study of outcomes in Oakland County, MI. Monte Carlo simulation (n = 10,000) and sensitivity analyses (n = 40) were used to assess median and the empiric 95% confidence intervals [CIs] for incremental survival with either intervention. The baseline model, calibrated to the characteristics of the input-data community, established that, for private-residence cardiac arrests, 40.8% of cardiac arrest bystanders were trained in CPR; however, only 25.7% performed CPR. This yielded 4.81% survival (95% CI = 4.72 to 4.89). Modeling the impact on the baseline training level with increased CPR performance among trainees indicated that 75% of private-residence trained bystanders would need to perform CPR in order to reach a minimally significant improvement in survival (5.02%; 95% CI = 4.94 to 5.15). Similarly, targeted CPR training that would result in a significant survival benefit (to 5.01%; 95% CI = 4.93 to 5.09) would require that 70.8% of bystanders be trained. CPR training programs that focus on yielding 75% of trainees who perform CPR in the event of witnessing an arrest would have equivalent results to mass CPR training programs that result in 70% of bystanders being trained in CPR. However, the minimal survival benefit associated with these programs (around 0.2%) may prove either method costly with minimal effect.


Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila.
On the basis of electrophysiological analysis of Shaker mutants, the Shaker locus of Drosophila melanogaster has been proposed to encode a structural component of a voltage-dependent potassium channel, the A channel. Unlike sodium channels, acetylcholine receptors, and calcium channels, K+ channels have not been purified biochemically. To facilitate biochemical studies of a K+ channel, genomic DNA from the Shaker locus has been cloned. Rearrangements in five Shaker mutants have been mapped to a 60-kilobase segment of the genome. Four complementary DNA clones have been analyzed. These clones indicate that the Shaker gene contains multiple exons distributed over at least 65 kilobases of genomic DNA in the region where the mutations mapped. Furthermore, the gene may produce several classes of alternatively spliced transcripts. Two of the complementary DNA clones have been sequenced and their sequences support the hypothesis that Shaker encodes a component of a K+ channel.


Shared genetic factors in migraine and depression: evidence from a genetic isolate.
To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases. Subjects were 2,652 participants of the Erasmus Rucphen Family genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls. We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval [CI] 0.98-1.70) for MO and 1.70 (95% CI 1.28-2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA. There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors.


Evaluation of three high abundance protein depletion kits for umbilical cord serum proteomics.
High abundance protein depletion is a major challenge in the study of serum/plasma proteomics. Prior to this study, most commercially available kits for depletion of highly abundant proteins had only been tested and evaluated in adult serum/plasma, while the depletion efficiency on umbilical cord serum/plasma had not been clarified. Structural differences between some adult and fetal proteins (such as albumin) make it likely that depletion approaches for adult and umbilical cord serum/plasma will be variable. Therefore, the primary purposes of the present study are to investigate the efficiencies of several commonly-used commercial kits during high abundance protein depletion from umbilical cord serum and to determine which kit yields the most effective and reproducible results for further proteomics research on umbilical cord serum. The immunoaffinity based kits (PROTIA-Sigma and 5185-Agilent) displayed higher depletion efficiency than the immobilized dye based kit (PROTBA-Sigma) in umbilical cord serum samples. Both the PROTIA-Sigma and 5185-Agilent kit maintained high depletion efficiency when used three consecutive times. Depletion by the PROTIA-Sigma Kit improved 2DE gel quality by reducing smeared bands produced by the presence of high abundance proteins and increasing the intensity of other protein spots. During image analysis using the identical detection parameters, 411 ± 18 spots were detected in crude serum gels, while 757 ± 43 spots were detected in depleted serum gels. Eight spots unique to depleted serum gels were identified by MALDI- TOF/TOF MS, seven of which were low abundance proteins. The immunoaffinity based kits exceeded the immobilized dye based kit in high abundance protein depletion of umbilical cord serum samples and dramatically improved 2DE gel quality for detection of trace biomarkers.


[Primary CNS Lymphoma: bibliographical review and experience at the Hospital of Navarre in the last 5 years (2000-2004)].
Primary cerebral lymphoma (Primary CNS Lymphoma, PCNSL) is an aggressive non-Hodgkin lymphoma that originates in the central nervous system without evidence of lymphoma in any other localization at the time of diagnosis. Primary cerebral lymphomas are less well-known and are characterized than their homologues the systemic lymphomas, as they are an entity whose frequency was scarce until a few decades ago. However, the great rise in incidence that this pathology has undergone over the last three decades, and which is still unexplained, makes more studies necessary to better understand the etiopathology of this entity. Thanks to the new systems of treatment, the prognosis of this pathology has improved significantly in recent years. Nonetheless, treatment of primary cerebral lymphoma continues to give rise to numerous controversies at present due to its high neurotoxicity in patients over 60 years of age, a group of patients frequently affected by this pathology. To resolve these and other questions it is necessary to deep in the study of primary cerebral lymphoma and to carry out high quality clinical trials.


Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.
A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.


Cardiovascular disease risk factors in menopausal Jamaican black women after hysterectomy and bilateral oophorectomy: an observational study.
To determine differences in prevalence of cardiovascular risks and diseases in black Jamaican postmenopausal women who had hysterectomy (hysgroup) compared with those without (control). Eight hundred and nine (809) women (hysterectomized (HYSGRP) = 403; non-hysterectomized (controls) = 406) were enrolled. Sociodemographic information and lifestyle history, measured blood pressure, waist hip ratio, body mass index, fasting blood glucose, total and HDL cholesterol were obtained. Of the 809 women, complete cardiovascular risk data were available in 341 controls and 328 in the HYSGRP group. There was no difference in mean age, blood pressure and body mass indices between the subjects excluded and the subjects in the data analytical sample. A significantly lower proportion of women in the control group exercised, attained post-secondary education and were of higher parity. Systolic (mean diference with 95% CI; 6 (3, 9) mmHg and diastolic (3 (1, 5) mmHg) blood pressure were lower in the HYSGRP compared with controls but total cholesterol (0.2 (0.07 to 0.4) mmol/L was greater HDL cholesterol was not different between both groups 1.3 mmol/L (SD 0.3) vs 1.3 mmol/L [SD 0.4] (p = 0.8435). There was no difference in the prevalence of diabetes, hypertension and high waist-hip ratio in hysterectomized women compared with controls adjusting for hormone replacement therapy usage, cigarette smoking, exercise and educational status. Within the HYSGRP there was also no diference in cardiovascular disease or risk in women who had bilateral oophorectomy compared with women who had at least an ovary preserved at time of operation. Hysterectomy was not associated with an increased risk of cardiovascular disease. This must be taken cautiously since data did not allow for analysis on duration of menopause.


Intragenic Deletions of GNAS in Pseudohypoparathyroidism Type 1A Identify a New Region Affecting Methylation of Exon A/B.
Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.


Axis of ageing: telomeres, p53 and mitochondria.
Progressive DNA damage and mitochondrial decline are both considered to be prime instigators of natural ageing. Traditionally, these two pathways have been viewed largely in isolation. However, recent studies have revealed a molecular circuit that directly links DNA damage to compromised mitochondrial biogenesis and function via p53. This axis of ageing may account for both organ decline and disease development associated with advanced age and could illuminate a path for the development of relevant therapeutics.


Transcriptomics and in vivo tests reveal novel mechanisms underlying endocrine disruption in an ecological sentinel, Nucella lapillus.
Anthropogenic endocrine disruptors now contaminate all environments globally, with concomitant deleterious effects across diverse taxa. While most studies on endocrine disruption (ED) have focused on vertebrates, the superimposition of male sexual characteristics in the female dogwhelk, Nucella lapillus (imposex), caused by organotins, provides one of the most clearcut ecological examples of anthropogenically induced ED in aquatic ecosystems. To identify the underpinning mechanisms of imposex for this 'nonmodel' species, we combined Roche 454 pyrosequencing with custom oligoarray fabrication inexpensively to both generate gene models and identify those responding to chronic tributyltin (TBT) treatment. The results supported the involvement of steroid, neuroendocrine peptide hormone dysfunction and retinoid mechanisms, but suggested additionally the involvement of putative peroxisome proliferator-activated receptor (PPAR) pathways. Application of rosiglitazone, a well-known vertebrate PPARγ ligand, to dogwhelks induced imposex in the absence of TBT. Thus, while TBT-induced imposex is linked to the induction of many genes and has a complex phenotype, it is likely also to be driven by PPAR-responsive pathways, hitherto not described in invertebrates. Our findings provide further evidence for a common signalling pathway between invertebrate and vertebrate species that has previously been overlooked in the study of endocrine disruption.


Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1.
Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed.


Frequency of Pregnancy Related Cancer: A Population Based Linkage Study in Lombardy, Italy.
The aims of this study were to estimate the occurrence of pregnancy-associated cancer overall and by site, to evaluate if the risk increases over time, and to investigate some major determinants. This is a population-based linkage study using the regional hospital discharge forms [Scheda di Dimissione Ospedaliera (SDO)] database of Lombardy, Italy, a region with 10 million inhabitants. All resident women with a SDO reporting a birth or abortion between 2001 and 2012 were identified. Pregnancy-associated cancers were defined as a cancer occurring during pregnancy or within 12 months after pregnancy and were identified by selecting all SDOs reporting a first diagnosis of cancer. Risk of developing a pregnancy-related cancer was calculated as the ratio of the number of pregnancy-related cancers to the total number of pregnancies. The effect of potential predictors on the risk was estimated using a logistic regression model, and odds ratios (OR) were estimated. During the period 2001-2012, the risk of pregnancy-related cancer was 122.9 per 100,000 pregnancies. The most common cancers were breast cancer (479 cases, 39.9/100,000 pregnancies), thyroid cancer (186 cases, 15.5/100,000), and lymphomas (157 cases, 13.1/100,000). Skin cancer accounted for 177 cases (14.8/100,000), half of which were melanomas. The risk of developing a pregnancy-related cancer increased significantly with age, from 60 of 100,000 for women less than 30 years old to 265 of 100,000 for women aged more than 40 years. Italian women had a higher risk than foreign ones (OR, 1.6), and the pregnancy outcome was more frequently an abortion (OR, 1.2), whereas no trend in risk was observed with calendar year (P = 0.249). This study confirms previously reported incidence estimates but does not show increases over time.


Mapping of bacterial biofilm local mechanics by magnetic microparticle actuation.
Most bacteria live in the form of adherent communities forming three-dimensional material anchored to artificial or biological surfaces, with profound impact on many human activities. Biofilms are recognized as complex systems but their physical properties have been mainly studied from a macroscopic perspective. To determine biofilm local mechanical properties, reveal their potential heterogeneity, and investigate their relation to molecular traits, we have developed a seemingly new microrheology approach based on magnetic particle infiltration in growing biofilms. Using magnetic tweezers, we achieved what was, to our knowledge, the first three-dimensional mapping of the viscoelastic parameters on biofilms formed by the bacterium Escherichia coli. We demonstrate that its mechanical profile may exhibit elastic compliance values spread over three orders of magnitude in a given biofilm. We also prove that heterogeneity strongly depends on external conditions such as growth shear stress. Using strains genetically engineered to produce well-characterized cell surface adhesins, we show that the mechanical profile of biofilm is exquisitely sensitive to the expression of different surface appendages such as F pilus or curli. These results provide a quantitative view of local mechanical properties within intact biofilms and open up an additional avenue for elucidating the emergence and fate of the different microenvironments within these living materials.


The DNA Cytosine Deaminase APOBEC3B is a Molecular Determinant of Platinum Responsiveness in Clear Cell Ovarian Cancer.
Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention. APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages. One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues. These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.


Network characterization of the Entangled Model for sustainability indicators. Analysis of the network properties for scenarios.
Policy-makers require strategies to select a set of sustainability indicators that are useful for monitoring sustainability. For this reason, we have developed a model where sustainability indicators compete for the attention of society. This model has shown to have steady situations where a set of sustainability indicators are stable. To understand the role of the network configuration, in this paper we analyze the network properties of the Entangled Sustainability model. We have used the degree distribution, the clustering coefficient, and the interaction strength distribution as main measures. We also analyze the network properties for scenarios compared against randomly generated scenarios. We found that the stable situations show different characteristics from the unstable transitions present in the model. We also found that the complex emergent feature of sustainability shown in the model is an attribute of the scenarios, however, the randomly generated scenarios do not present the same network properties.


Plant species composition alters the sign and strength of an emergent multi-predator effect by modifying predator foraging behaviour.
The prediction of pest-control functioning by multi-predator communities is hindered by the non-additive nature of species functioning. Such non-additivity, commonly termed an emergent multi-predator effect, is known to be affected by elements of the ecological context, such as the structure and composition of vegetation, in addition to the traits of the predators themselves. Here we report mesocosm experiments designed to test the influence of plant density and species composition (wheat monoculture or wheat and faba bean polyculture) on the emergence of multi-predator effects between Adalia bipunctata and Chrysoperla carnea, in their suppression of populations of the aphid Metopolophium dirhodum. The mesocosm experiments were followed by a series of behavioural observations designed to identify how interactions among predators are modified by plant species composition and whether these effects are consistent with the observed influence of plant species composition on aphid population suppression. Although plant density was shown to have no influence on the multi-predator effect on aphid population growth, plant composition had a marked effect. In wheat monoculture, Adalia and Chrysoperla mixed treatments caused greater suppression of M. dirhodum populations than expected. However this positive emergent effect was reversed to a negative multi-predator effect in wheat and faba bean polyculture. The behavioural observations revealed that although dominant individuals did not respond to the presence of faba bean plants, the behaviour of sub-dominants was affected markedly, consistent with their foraging for extra-floral nectar produced by the faba bean. This interaction between plant composition and predator community composition on the foraging behaviour of sub-dominants is thought to underlie the observed effect of plant composition on the multi-predator effect. Thus, the emergence of multi-predator effects is shown to be strongly influenced by plant species composition, mediated, in this case, by the provision of extra-floral nectar by one of the plant species.


Parity-dependent oscillations in collisional polarization transfer: CN(A²Π, v = 4) + Ar.
We report the first systematic experimental and theoretical study of the state-to-state transfer of rotational angular momentum orientation in a (2)Π-rare gas system. CN(X(2)Σ(+)) was produced by pulsed 266 nm photolysis of ICN in a thermal bath (296 K) of Ar collider gas. A pulsed circularly polarized tunable dye laser prepared CN(A(2)Π, v = 4) in two fully state-selected initial levels, j = 6.5 F1e and j = 10.5 F2f, with a known laboratory-frame orientation. Both the prepared levels and a range of product levels, j' F1e and j' F2f, were monitored using the circular polarized output of a tunable diode laser via cw frequency-modulated (FM) spectroscopy in stimulated emission on the CN(A-X) (4,2) band. The FM Doppler lineshapes for co-rotating and counter-rotating pump-and-probe geometries reveal the time-dependence of the populations and orientations. Kinetic fitting was used to extract the state-to-state population transfer rate constants and orientation multipole transfer efficiencies (MTEs), which quantify the degree of conservation of initially prepared orientation in the product level. Complementary full quantum scattering (QS) calculations were carried out on recently computed ab initio potential energy surfaces. Collision-energy-dependent tensor cross sections for ranks K = 0 and 1 were computed for transitions from both initial levels to all final levels. These quantities were integrated over the thermal collision energy distribution to yield predictions of the experimentally observed state-to-state population transfer rate constants and MTEs. Excellent agreement between experiment and theory is observed for both measured quantities. Dramatic oscillations in the MTEs are observed, up to and including changes in the sign of the orientation, as a function of even/odd Δj within a particular spin-orbit and e/f manifold. These oscillations, along with those also observed in the state-to-state rate constants, reflect the rotational parity of the final level. In general, parity-conserving collisions conserve rotational orientation, while parity-changing collisions result in large changes in the orientation. The QS calculations show that the dynamics of the collisions leading to these different outcomes are fundamentally different. We propose that the origin of this behavior lies in interferences between collisions that sample the even and odd-λ terms in the angular expansions of the PESs.


Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs.
The thermodynamics of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estimated by potential of mean force calculations. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol(-1). Decomposing the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol(-1) compared to non-fluorinated analogs. This is attributed to stabilizing C-F(...)H-N dipolar interactions and stronger N(...)H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first experimental evidence for nitrogen-containing heterocylces as bioisosteres of aromatic rings bearing fluorine atoms.


Saccharide Libraries as Potential Templates for Regio- and Chiroselective Introduction of Two Functional Groups into [60]Fullerene.
This paper reports regio- and chiroselective introduction of two boronic acid groups into [60]fullerene controlled by a saccharide used as a template molecule. The double [4+2] cycloadditions between [60]fullerene and 1:2 saccharide-boronic acid complexes 6-9 afforded [60]fullerene-bisadducts 12. Their structures were identified on the basis of (1)H and (13)C NMR, UV-vis, and CD spectroscopy, mass spectrometry, and chiral HPLC analysis. When 3-O-methyl-D-glucose (4) was used as the template molecule, high regioselectivity was achieved which gave trans-4 isomer 12a as a main isomer in 72.5% yield. The chiro- as well as regioselective preparation of e isomer 12c was attained in 81.4% ee from the 55.7% yield racemic mixture by the reaction using the D-mannitol-3,4-carbonate template (3). When the enantiomers, D-threitol (D-2) and L-threitol (L-2) were used as the templates, cis-3 isomers 12b and ent-12b with opposite chirality were yielded in 44.2 and 45.2% ee, respectively. On the other hand, 1-O-methyl-alpha-D-mannopyranoside template (5) featured nonselective cycloaddition.


Prognostic factors for improved physical and emotional functioning one year after interdisciplinary rehabilitation in patients with chronic pain: Results from a national quality registry in Sweden.
To investigate prognostic factors for physical and emotional functioning following interdisciplinary multimodal pain rehabilitation, by targeting patients' baseline characteristics and health measures. A prospective cohort of 2,876 patients from 38 specialist clinics across Sweden, who were completing interdisciplinary multimodal pain rehabilitation programmes, was followed through the Swedish Quality Registry for Pain Rehabilitation, from initial assessment to 12-month follow-up. Using logistic regression, baseline data were regressed to predict improvement in Physical functioning and Emotional functioning, fused by principal component analyses using the 36-item Short Form Health Survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS). Employment status emerged as having the largest effect sizes in both Physical functioning and Emotional functioning; Working: odds ratio (OR) 2.05 (95% confidence interval (95% CI) 1.64-2.56) and OR 1.59 (95% CI 1.27-1.98), respectively. Strong beliefs in restored health, better initial emotional health, lower levels of pain and pain interference, and younger age all predicted Physical functioning. European origin, higher levels of general activity, and sense of life control all predicted Emotional functioning. Worse initial physical and emotional health predicted the corresponding dependent outcomes. Employment was consistently found to be an important prognostic factor, suggesting the significance of avoiding delay in interdisciplinary multimodal pain rehabilitation. A positive treatment expectancy was of importance. In general, multidimensional measures indicated that better initial status was more favourable; however, inconsistency implies a complex prognostic picture.


Hypercalcemic Disorders in Children.
Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.


The view from the interventionalist.
The development of percutaneous valve replacement has broadened the procedural interface between interventional cardiologists and their cardiothoracic surgical colleagues. Our relationship is no longer restricted to the arena of coronary artery disease, and opportunities now exist to share the care of large numbers of high surgical risk patients with severe aortic stenosis. These complex professional relationships have a mutual dependence and many shared objectives that should be centred upon the optimal care of cardiac patients. However, the continuing evolution of technology demands that these relationships evolve with time. A failure to understand this need for mutual change and increased cooperation has previously led to a sense of competition and Departmental separation between cardiac intervention and surgery. These fractured relationships ultimately limit the quality of care that we deliver to our patients.


How Reliable Are Administrative Data for Capturing Stroke Patients and Their Care.
The reliability of diagnostic coding of acute stroke and transient ischemic attack (TIA) in administrative data is uncertain. The purpose of this study is to determine the agreement between administrative data sources and chart audit for the identification of stroke type, stroke risk factors, and the use of hospital-based diagnostic procedures in patients with stroke or TIA. Medical charts for a population-based sample of patients (n = 14,508) with ischemic stroke, intracerebral hemorrhage (ICH), or TIA discharged from inpatient and emergency departments (ED) in Ontario, Canada, between April 1, 2012 and March 31, 2013, were audited by trained abstractors. Audited data were linked and compared with hospital administrative data and physician billing data. The positive predictive value (PPV) of hospital administrative data and kappa agreement for the reporting of stroke type were calculated. Kappa agreement was also determined for stroke risk factors and for select stroke-related procedures. The PPV for stroke type in inpatient administrative data ranged from 89.5% (95% CI 88.0-91.0) for TIA, 91.9% (95% CI 90.2-93.5) for ICH, and 97.3% (95% CI 96.9-97.7) for ischemic stroke. For ED administrative data, PPV varied from 78.8% (95% CI 76.3-81.2) for ischemic, 86.3% (95% CI 76.8-95.7) for ICH, and 95.3% (95% CI 94.6-96.0) for TIA. The chance-corrected agreement between the audited and administrative data was good for atrial fibrillation (k = 0.60) and very good for diabetes (k = 0.86). Hospital administrative data combined with physician billing data more than doubled the observed agreement for carotid imaging (k = 0.65) and echocardiography (k = 0.66) compared to hospital administrative data alone. Inpatient and ED administrative data were found to be reliable in the reporting of the International Classification of Diagnosis, 10th revision, Canada (ICD-10-CA)-coded ischemic stroke, ICH and TIA, and for the recording of atrial fibrillation and diabetes. The combination of physician billing data with hospital administrative data greatly improved the capture of some diagnostic services provided to inpatients.


Modelling social vulnerability in sub-Saharan West Africa using a geographical information system.
In recent times, disasters and risk management have gained significant attention, especially with increasing awareness of the risks and increasing impact of natural and other hazards especially in the developing world. Vulnerability, the potential for loss of life or property from disaster, has biophysical or social dimensions. Social vulnerability relates to societal attributes which has negative impacts on disaster outcomes. This study sought to develop a spatially explicit index of social vulnerability, thus addressing the dearth of research in this area in sub-Saharan Africa. Nineteen variables were identified covering various aspects. Descriptive analysis of these variables revealed high heterogeneity across the South West region of Nigeria for both the state and the local government areas (LGAs). Feature identification using correlation analysis identified six important variables. Factor analysis identified two dimensions, namely accessibility and socioeconomic conditions, from this subset. A social vulnerability index (SoVI) showed that Ondo and Ekiti have more vulnerable LGAs than other states in the region. About 50% of the LGAs in Osun and Ogun have a relatively low social vulnerability. Distribution of the SoVI shows that there are great differences within states as well as across regions. Scores of population density, disability and poverty have a high margin of error in relation to mean state scores. The study showed that with a geographical information system there are opportunities to model social vulnerability and monitor its evolution and dynamics across the continent.


Experiences and conceptualizations of sexual debut from the narratives of South African men and women in the context of HIV/AIDS.
Given the pivotal role of first sex in the development of sexual and reproductive health (SRH) practices, there is a need for more contextualised and nuanced understandings of young people's early sexual debut experiences. This study used sexual history narratives to investigate how South African men and women experience and attribute meaning to their sexual debut, and their SRH practices. In light of the gendered disparities among young people's SRH awareness and risk, differences between men and women's narratives of sexual debut were assessed. Fifty sexual history interviews were conducted with men and 25 sexual history interviews with women, with participants purposively sampled from three age categories, a range of cultural and racial backgrounds and urban and rural sites across five provinces. Narrative interviews were designed to elicit stories around participants' early knowledge of sex and sexual experimentation, their range of sexual relationships and SRH practices. The data were analysed using a thematic approach. Participants generally reflected on their early sexual experiences with feelings of inadequacy and disappointment. While men appeared to hold greater decision-making power than women at sexual debut, descriptions of men's early sexual experiences were often characterised by respect, intimacy and vulnerability. Many men attributed the timing of their sexual debut to peer pressure, which typically generated higher social status and rarely included consideration of the need to practice safer sex. Several women felt pressured by their partner to sexually debut, which could have informed their perceptions of men being sexually controlling and aggressive. The study demonstrates the value of a narrative approach for generating insights on young people's sexual debut experiences and SRH practices, and the underlying gendered norms and expectations that shape these. The findings indicate the need for gender transformative HIV interventions to take into the diversity of young people's SRH needs and social realities.


Mapping of intracellular pH in the in vivo rodent heart using hyperpolarized [1-13C]pyruvate.
To demonstrate the feasibility of mapping intracellular pH within the in vivo rodent heart. Alterations in cardiac acid-base balance can lead to acute contractile depression and alterations in Ca2+ signaling. The transient reduction in adenosine triphosphate (ATP) consumption and cardiac contractility may be initially beneficial; however, sustained pH changes can be maladaptive, leading to myocardial damage and electrical arrhythmias. Spectrally selective radiofrequency (RF) pulses were used to excite the HCO3- and CO2 resonances individually while preserving signal from the injected hyperpolarized [1-13 C]pyruvate. The large flip angle pulses were placed within a three-dimensional (3D) imaging acquisition, which exploited CA-mediated label exchange between HCO3- and CO2 . Images at 4.5 × 4.5 × 5 mm3 resolution were obtained in the in vivo rodent heart. The technique was evaluated in healthy rodents scanned at baseline and during high cardiac workload induced by dobutamine infusion. The intracellular pH was measured to be 7.15 ± 0.04 at baseline, and decreased to 6.90 ± 0.06 following 15 min of continuous β-adrenergic stimulation. Volumetric maps of intracellular pH can be obtained following an injection of hyperpolarized [1-13 C]pyruvate. The new method is anticipated to enable assessment of stress-inducible ischemia and potential ventricular arrythmogenic substrates within the ischemic heart. Magn Reson Med 77:1810-1817, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.