2-Year Outcomes After Iliofemoral Self-Expanding Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis Deemed Extreme Risk for Surgery.
We reported favorable 1-year outcomes in patients unsuitable for surgery who underwent self-expanding transcatheter aortic valve replacement (TAVR) compared with an objective performance goal. Longer-term outcomes in these patients are not known. This study sought to evaluate the 2-year safety and efficacy in patients with severe aortic stenosis (AS) at extreme risk of surgery treated with self-expanding TAVR. We performed a prospective, multicenter, controlled, nonrandomized investigation of self-expanding TAVR in patients with severe AS and prohibitive surgical risk. We report the 2-year clinical outcomes in these patients. A total of 489 extreme-risk patients were treated transfemorally with a self-expanding aortic bioprosthesis at 41 centers. The rate of all-cause mortality or major stroke was 38.0% at 2 years (all-cause mortality, 36.5%; major stroke, 5.1%). The rates of all-cause mortality, cardiovascular mortality, and major stroke were 36.6%, 26.2%, and 5.1%, respectively, at 2 years. Between 1 and 2 years, the incremental all-cause mortality, cardiovascular mortality, and major stroke rates were 12.3%, 7.9%, and 0.8%, respectively. Multivariable predictors of all-cause mortality at 2 years included the presence of coronary artery disease and admission from an assisted living center. A Society of Thoracic Surgeons score >15% was also predictive of 2-year all-cause mortality. At 2 years, 94% of patients had New York Heart Association functional class I or II symptoms. The frequency of moderate or severe paravalvular regurgitation (4.3% at 1 year; 4.4% at 2 years) was unchanged between the first and second year. Patients with severe AS at extreme surgical risk treated with self-expanding TAVR continued to show good clinical outcomes and hemodynamic valve performance at 2 years. The presence of comorbid conditions rather than valve performance affected 2-year outcomes in these patients. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902).


The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition.
Gene expression data derived from clinical cancer specimens provide an opportunity to characterize cancer-specific transcriptional programs. Here, we present an analysis delineating a correlation-based gene expression landscape of breast cancer that identifies modules with strong associations to breast cancer-specific and general tumor biology. Modules of highly connected genes were extracted from a gene co-expression network that was constructed based on Pearson correlation, and module activities were then calculated using a pathway activity score. Functional annotations of modules were experimentally validated with an siRNA cell spot microarray system using the KPL-4 breast cancer cell line, and by using gene expression data from functional studies. Modules were derived using gene expression data representing 1,608 breast cancer samples and validated in data sets representing 971 independent breast cancer samples as well as 1,231 samples from other cancer forms. The initial co-expression network analysis resulted in the characterization of eight tightly regulated gene modules. Cell cycle genes were divided into two transcriptional programs, and experimental validation using an siRNA screen showed different functional roles for these programs during proliferation. The division of the two programs was found to act as a marker for tumor protein p53 (TP53) gene status in luminal breast cancer, with the two programs being separated only in luminal tumors with functional p53 (encoded by TP53). Moreover, a module containing fibroblast and stroma-related genes was highly expressed in fibroblasts, but was also up-regulated by overexpression of epithelial-mesenchymal transition factors such as transforming growth factor beta 1 (TGF-beta1) and Snail in immortalized human mammary epithelial cells. Strikingly, the stroma transcriptional program related to less malignant tumors for luminal disease and aggressive lymph node positive disease among basal-like tumors. We have derived a robust gene expression landscape of breast cancer that reflects known subtypes as well as heterogeneity within these subtypes. By applying the modules to TP53-mutated samples we shed light on the biological consequences of non-functional p53 in otherwise low-proliferating luminal breast cancer. Furthermore, as in the case of the stroma module, we show that the biological and clinical interpretation of a set of co-regulated genes is subtype-dependent.


High burden of prediabetes and diabetes in three large cities in South Asia: The Center for cArdio-metabolic Risk Reduction in South Asia (CARRS) Study.
To estimate the prevalence of, and assess factors associated with, diabetes and prediabetes in three South Asian cities. Using a multi-stage cluster random sample representative of each city, 16,288 subjects aged ≥20 years (Chennai: 6906, Delhi: 5365 and Karachi: 4017) were recruited to the Centre for cArdio-metabolic Risk Reduction in South-Asia (CARRS) Study. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) were measured in 13720 subjects. Prediabetes was defined as FPG 100-125 mg/dl (5.6-6.9 mmol/l) and/or HbA1c 5.7-6.4% (39-46 mmol/mol) and diabetes as self-report and/or drug treatment for diabetes and/or FPG≥126 mg/dl (≥7.0 mmol/l) and/or HbA1c≥6.5% (48 mmol/mol). We assessed factors associated with diabetes and prediabetes using polytomous logistic regression models. Overall 47.3-73.1% of the population had either diabetes or prediabetes: Chennai 60.7% [95%CI: 59.0-62.4%] (diabetes - 22.8% [21.5-24.1%], prediabetes - 37.9% [36.1-39.7%]); Delhi 72.7% [70.6-74.9%] (diabetes - 25.2% [23.6-26.8%], prediabetes - 47.6% [45.6-49.5%]); and Karachi 47.4% [45.7-49.1%]; (diabetes - 16.3% [15.2-17.3%], prediabetes - 31.1% [29.5-32.8%], respectively). Proportions of self-reported diabetes were 55.1%, 39.0%, and 48.0% in Chennai, Delhi, and Karachi, respectively. City, age, family history of diabetes, generalized obesity, abdominal obesity, body fat, high cholesterol, high triglyceride, and low HDL cholesterol levels were each independently associated with prediabetes, while the same factors plus waist-to-height ratio and hypertension were associated with diabetes. Six in ten adults in large South Asian cities have either diabetes or prediabetes. These data call for urgent action to prevent diabetes in South Asia.


Growth hormone secretion in patients with Turner's syndrome as determined by time series analysis.
Twenty-four-hour growth hormone (GH) profiles in 26 girls with Turner's syndrome were compared with those of 26 normally growing short children and 24 slowly growing short children. All children were prepubertal and below 12 years of age. A subgroup of 13 girls was treated with ethinyl estradiol and a 24-h GH profile was reassessed. In an additional group of 45 girls with Turner's syndrome (aged 6.7-18.9 years) the effect of age, spontaneous breast development and ethinyl estradiol treatment was studied. The profiles were assessed by Fourier analysis. The oscillatory activity and the mean 24-h GH concentration were similar in children with Turner's syndrome and the normally growing short children, in contrast to lower levels in the slowly growing short children. The periodicity of GH secretion was similar in all groups. In the longitudinal study, ethinyl estradiol treatment resulted in a significant increase in pulse amplitude, but not in periodicity. In the cross-sectional study there was no significant difference between the subgroups of girls with either presence or absence of breast development or ethinyl estradiol treatment. GH secretion was not significantly related to age, height in standard deviation score or height velocity. These data imply that there is no abnormality in GH secretion in girls with Turner's syndrome.


Correlates of daytime sleepiness in patients with posttraumatic stress disorder and sleep disturbance.
To assess the correlates of daytime sleepiness in patients with a lifetime diagnosis of posttraumatic stress disorder (PTSD) and ongoing sleep disturbance not due to sleep apnea or other diagnosed sleep disorders. The sample consisted of 26 veterans receiving mental health care at the Minneapolis VA Medical Center, Minneapolis, Minnesota. The Epworth Sleepiness Scale was the primary outcome measure. Other sleep-related instruments consisted of the Pittsburgh Sleep Quality Scale, a daily sleep log, and daily sleep actigraphy. In addition, data included 3 symptom ratings (Posttraumatic Stress Disorder Checklist, Clinician Administered PTSD Scale [CAPS], and Beck Depression Inventory). Data were collected from 2003 to 2005. Current and lifetime PTSD diagnoses were based on DSM-IV criteria and were obtained by experienced psychiatrists using the CAPS interview. Univariate analyses showed that daytime sleepiness on the Epworth Sleepiness Scale was associated with daytime dysfunction on the Pittsburgh Sleep Quality Index (P < .001), less use of sleeping medication (P = .02), and more self-rated posttraumatic symptoms (P = .05). Within posttraumatic symptom categories, hypervigilance symptoms were more correlated with daytime sleepiness (P = .03) than were reexperiencing and avoidance symptoms (P = .09 for both). In this selected sample, daytime sleepiness was most strongly and independently associated with daytime dysfunction.


Crisis intervention for nurses.
Cancer diagnoses and treatments can be crisis-causing events that overwhelm the usual coping abilities of patients and their families. Oncology nurses constantly are observing and attending to patients' diverse needs, ranging from biomedical to emotional, social, and psychological. Nurses have the chance to be first responders in times of patient crises, as they are in the position to recognize the crisis, respond effectively, and transform the crisis into a pivotal learning experience. This article discusses a way to think about patient and family crises that empowers nurses to respond in a manner appropriate to the cultural context and respectful of the individual space of the patient.


Reversal of Anticoagulants in Critical Care.
There has seen an increase in anticoagulant consumption worldwide over the past few decades. With this widespread utilization of anticoagulants, clinicians are increasingly likely to encounter situations where anticoagulants would need to be withheld. This includes emergency and elective procedures or surgeries as well as major or minor bleeding as a direct result of over anticoagulation or consequent to other intercurrent illnesses such as sepsis or trauma with multiorgan failure, where the anticoagulant may contribute to coagulation abnormalities. Clinicians are required to have a thorough understanding of the indications for anticoagulant prescription, drug interactions and monitoring, indications and options of reversal of anticoagulation and management of bleeding in the situations described above. Once the acute process is managed, the ongoing need and timing of reinitiation of anticoagulation is also crucial. This article provides an overview on the indications for reversal of anticoagulation, the agents used for reversal and the timing of reinitiation of anticoagulants. Chacko B, Peter JV, Subramani K. Reversal of Anticoagulants in Critical Care. Indian J Crit Care Med 2019;23(Suppl 3):S221-S225.


Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice.
Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented. The available literature was reviewed. The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future. The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3-4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.


Catheter-based closure of aortic and mitral paravalvular leaks: existing techniques and new frontiers.
Significant paravalvular leak (PVL) complicates between 6% and 15% of valve replacements and can result in heart failure and hemolysis. Paravalvular leak can be effectively treated with repeat surgery; however, these procedures are associated with significant operative morbidity. Percutaneous PVL closure is increasingly being utilized as the first line therapy for symptomatic patients, but efficacy may be limited by the lack of dedicated closure devices. This article will review the etiology and prevalence of PVL, discuss outcomes with surgical closure, describe the mounting data supporting percutaneous interventions, and highlight areas for future research emphasizing the need for new dedicated closure devices. Percutaneous PVL closure can be safely accomplished in the majority of patients with PVL thereby avoiding the risks associated with repeat surgical intervention. However, percutaneous interventions are associated with higher rates of persistent leakage in part due to off-label use of devices intended for other applications. Efforts to develop devices specifically intended for PVL closure are needed to further improve outcomes for percutaneous PVL closure.


Tobacco industry and public health responses to state and local efforts to end tobacco sales from 1969-2020.
In June 2019, Beverly Hills, California, became the first American city in the 21st century to pass an ordinance ending the sale of most tobacco products, including cigarettes, and it is unlikely to be the last. Knowledge of previous efforts to ban tobacco sales in the US, both successful and unsuccessful, may help inform tobacco control advocates' approach to future efforts. We retrieved and analyzed archival tobacco industry documents. We confirmed and supplemented information from the documents with news media coverage and publicly available state and local government materials, such as meeting minutes and staff reports, related to proposed bans. We found 22 proposals to end the sale of cigarettes or tobacco products from 1969-2020 in the US. Proposals came from five states, twelve cities or towns, and one county. Most came from elected officials or boards of health, and were justified on public health grounds. In opposing tobacco sales bans, the tobacco industry employed no tactics or arguments that it did not also employ in campaigns against other tobacco control measures. Public health groups typically opposed sales ban proposals on the grounds that they were not evidence-based. This changed with Beverly Hills' 2019 proposal, with public health organizations supporting this and other California city proposals because of their likely positive health impacts. This support did not always translate into passage of local ordinances, as some city council members expressed reservations about the impact on small businesses. Tobacco control advocates are likely to encounter familiar tobacco industry tactics and arguments against tobacco sales ban proposals, and can rely on past experience and the results of a growing body of retail-related research to counter them. Considering how to overcome concerns about harming retailers will likely be vital if other jurisdictions are to succeed in ending tobacco sales.


Seroprevalence of Cytomegalo Virus (CMV) among pregnant women in Thika, Kenya.
The fetal consequences of CMV infection have made it one of the most serious infections contracted during pregnancy. Despite the posed teratogenic risk during pregnancy, there is no national screening test for CMV infection is available during pregnancy in Kenya. Thus little is known on its epidemiological data that is necessary for health planners and care providers. A cross sectional study was conducted at Thika district level 5 hospital, Kenya to investigate seroprevalence of CMV infections and associated possible risk factors among pregnant women. Structured questionnaires were used to gather socio-demographic data and ELISA was used to detect CMV infections using IgG and IgM. Out of 260 pregnant women, 201 (77.3%) were CMV IgG 21(8.1%) CMV IgM being on acute stage of the disease. Marital status (OR = 3.7533, 95% CI =3.0231-6.9631, P < 0.0001), parity (OR = 3.7533, 95% CI = 3.0231-6.9631, P < 0.0001), and education (OR = 3.7533, 95% CI = 3.0231-6.9631, P < 0.0001), history of blood transfusion (OR = 0.0374, 95% CI = 0.00120-0.1168, OR = 0.3804) were found to significantly influence seropostivity in univariate analysis. The 88.4% CMV prevalence rate being detected among pregnant women calls for vaccine and routine screening for CMV infections and its associated risk factors in this kind of settings.


Antimicrobial Resistance in Escherichia coli Recovered from Feedlot Cattle and Associations with Antimicrobial Use.
The objectives of this study were to estimate the prevalence of antimicrobial resistance (AMR) and to investigate the associations between exposures to antimicrobial drugs (AMDs) and AMR in fecal non-type specific Escherichia coli (NTSEC) recovered from a large population of feedlot cattle. Two-stage random sampling was used to select individually identified cattle for enrollment, which were sampled at arrival and then a second time later in the feeding period. Advanced regression techniques were used to estimate resistance prevalences, and to investigate associations between AMD exposures in enrolled cattle and penmates and AMR identified in NTSEC recovered from the second sample set. Resistance was most commonly detected to tetracycline, streptomycin, and sulfisoxazole, and was rarely identified for critically important AMDs. All cattle were exposed to AMDs in feed, and 45% were treated parenterally. While resistance prevalence generally increased during the feeding period, most AMD exposures were not significantly associated with AMR outcomes. Exposures of enrolled cattle to tetracycline were associated with increased resistance to tetracycline and trimethoprim sulfa, while beta-lactam exposures were associated with decreased likelihood of detecting streptomycin resistance. Pen-level AMD exposure measures were not associated with resistance outcomes. These findings suggest that tetracycline treatment of feedlot cattle can be associated with modest increases in risk for recovery of resistant NTSEC, but the numerous treatments with an advanced macrolide (tulathromycin) were not associated with detectable increases in resistance in NTSEC. All cattle were exposed to in-feed treatments of tetracycline and this could limit the ability to identify the full impact of these exposures, but these exposures varied for enrolled cattle varied, providing an opportunity to evaluate a dose response. While AMD exposures were not associated with detectably increased risks for resistance to critically important AMDs, rare resistance outcomes and infrequent exposure to other important AMDs (e.g., cephalosporins) limited our ability to rigorously investigate questions regarding factors that can influence resistance to these important AMDs.


Hereditary prostate cancer as a feature of Lynch syndrome.
Lynch Syndrome is an autosomal dominant condition characterized by early onset colorectal cancer (CRC) and is associated with cancers of the gastrointestinal and reproductive tracts. Germline mutations in DNA mismatch repair (MMR) genes have been causally associated with cancers of Lynch Syndrome. We investigated the occurrence of prostate cancer (PCa) in families with a history of colorectal cancer to assess prostate cancer as a feature of the Lynch Syndrome spectrum. Family pedigrees containing at least one CRC case as well as those meeting guidelines for Lynch Syndrome were identified and tumors were requested from participants who underwent radical prostatectomy (RP). Selected families were analyzed for association with type of PCa and clinical characteristics of aggressive disease. Microsatellite Instability (MSI) analysis was preformed on available tumors and correlated to loss of expression in MMR genes by immunohistochemical (IHC) staining. 95 individuals were identified as members of potential Lynch Syndrome families who underwent RP and 35 tumors from 31 families were received for MSI analysis. Two tumors from two unrelated families with known MMR mutations were MSI-high and one additional case from a third family was MSI-low. The remainder of the prostate cancer cases demonstrated no evidence of MSI. PCa incidence in families enriched for hereditary PCa with a history of Lynch Syndrome cancers is not strongly suggestive of the presence of an MMR mutation. However prostate tumors in known MMR mutation carriers did display MSI and loss of gene expression suggesting that PCa may arise in Lynch Syndrome due to defective DNA mismatch repair.


Light-intensity activity attenuates functional decline in older cancer survivors.
While moderate- to vigorous-intensity physical activities (MVPA) confer the greatest health benefits, evidence suggests that light-intensity activities are also beneficial, particularly for older adults and individuals with moderate to severe comorbidities. To examine cross-sectional and longitudinal associations between light-intensity activity and physical function in older cancer survivors at increased risk for age- and treatment-related comorbidities, including accelerated functional decline. The analysis included data from 641 breast, prostate, and colorectal cancer survivors (54% female) age 65 yr and older who participated in a 1-yr home-based diet and exercise intervention designed to reduce the rate of physical function decline. ANCOVA was used to compare means of physical function across levels of PA intensity (low-light [LLPA]: 1.5-2.0 METs; high-light [HLPA]: 2.1-2.9 METs; MVPA: ≥3.0 METs). In cross-sectional analyses, increasing tertiles of light-intensity activity were associated with higher scores for all three measures of physical function (all P values <0.005), after adjusting for age, sex, body mass index, comorbidity, symptoms, and MVPA. Associations were stronger for HLPA than for LLPA. Compared with survivors who had decreased MVPA or maintained stable MVPA and HLPA at the postintervention follow-up, those who had increased HLPA, but had decreased MVPA or maintained stable MVPA, reported higher physical function scores (LS means [95% confidence interval]: SF-36 Physical Function Subscale: -5.58 [-7.96 to -3.20] vs -2.54 [-5.83 to 0.75], P = 0.14; Basic Lower Extremity Function: -2.00 [-3.45 to -0.55] vs 0.28 [-1.72 to 2.28], P = 0.07; Advanced Lower Extremity Function: -2.58 [-4.00 to -1.15] vs 0.44 [-1.52 to 2.40], P = 0.01). Our findings suggest that increasing light-intensity activities, especially HLPA, may be a viable approach to reducing the rate of physical function decline in individuals who are unable or reluctant to initiate or maintain adequate levels of moderate-intensity activities.


Warm-Up Intensity Does Not Affect the Ergogenic Effect of Sodium Bicarbonate in Adult Men.
This study determined the influence of a high- (HI) versus low-intensity (LI) cycling warm-up on blood acid-base responses and exercise capacity following ingestion of sodium bicarbonate (SB; 0.3 g/kg body mass) or a placebo (PLA; maltodextrin) 3 hr prior to warm-up. Twelve men (21 ± 2 years, 79.2 ± 3.6 kg body mass, and maximum power output [Wmax] 318 ± 36 W) completed a familiarization and four double-blind trials in a counterbalanced order: HI warm-up with SB, HI warm-up with PLA, LI warm-up with SB, and LI warm-up with PLA. LI warm-up was 15 min at 60% Wmax, while the HI warm-up (typical of elites) featured LI followed by 2 × 30 s (3-min break) at Wmax, finishing 30 min prior to a cycling capacity test at 110% Wmax. Blood bicarbonate and lactate were measured throughout. SB supplementation increased blood bicarbonate (+6.4 mmol/L; 95% confidence interval, CI [5.7, 7.1]) prior to greater reductions with HI warm-up (-3.8 mmol/L; 95% CI [-5.8, -1.8]). However, during the 30-min recovery, blood bicarbonate rebounded and increased in all conditions, with concentrations ∼5.3 mmol/L greater with SB supplementation (p < .001). Blood bicarbonate significantly declined during the cycling capacity test at 110%Wmax with greater reductions following SB supplementation (-2.4 mmol/L; 95% CI [-3.8, -0.90]). Aligned with these results, SB supplementation increased total work done during the cycling capacity test at 110% Wmax (+8.5 kJ; 95% CI [3.6, 13.4], ∼19% increase) with no significant main effect of warm-up intensity (+0.0 kJ; 95% CI [-5.0, 5.0]). Collectively, the results demonstrate that SB supplementation can improve HI cycling capacity irrespective of prior warm-up intensity, likely due to blood alkalosis.


Wnt6 influences the viability of mouse embryonic palatal mesenchymal cells via the β-catenin pathway.
The embryological stages of palatal shelf elongation and elevation, mainly induced by the proliferation and extracellular matrix secretion of embryonic palatal mesenchymal (MEPM) cells, are essential for normal palatal development. Wingless-related MMTV integration site gene family (Wnt) signaling pathways serve key roles in craniofacial development and palate formation. Recent studies have indicated that Wnt6 participates in embryonic development of the palate, though its exact role in palate development remains unclear. In the present study, to investigate the role of Wnt6 during the stages of palatal shelves elongation and elevation, mouse MEPM cells were cultured from dissected palatal shelves at embryonic day 13.5. Results of an MTT assay and flow cytometric analysis demonstrated that treatment with recombinant Wnt6 increased the viability of MEPM cells (P<0.01) and the proportion of cells in the S and G2/M phases (P<0.01). Meanwhile, Wnt6 activated the β-catenin signaling pathway as indicated by the dual luciferase assay result, and blockade of the WNT/β-catenin pathway reduced the cytoactivity of Wnt6 in MEPM cells (P<0.01). Collectively, these findings indicate that Wnt6 promotes the vitality of MEPM cells by increasing the S + G2/M-phase cell population, potentially through activation of the β-catenin pathway during palatal shelf elongation and elevation.


Effect of soy saponin on the growth of human colon cancer cells.
To investigate the effect of extracted soybean saponins on the growth of human colon cancer cells. WiDr human colon cancer cells were treated with 150, 300, 600 or 1200 ppm of soy saponin to determine the effect on cell growth, cell morphology, alkaline phosphatase (AP) and protein kinase C (PKC) activities, and P53 protein, c-Fos and c-Jun gene expression. Soy saponin decreased the number of viable cells in a dose-dependent manner and suppressed 12-O-tetradecanol-phorbol-13-acetate-stimulated PKC activity (P < 0.05). Cells treated with saponins developed cytoplasmic vesicles and the cell membrane became rougher and more irregular in a dose-dependent manner, and eventually disassembled. At 600 and 1200 ppm, the activity of AP was increased (P < 0.05). However, the apoptosis markers such as c-Jun and c-Fos were not significantly affected by saponin. Soy saponin may be effective in preventing colon cancer by affecting cell morphology, cell proliferation enzymes, and cell growth.


Identification of the gene variations in human CD22.
CD22, a member of the immunoglobulin superfamily, is a B-cell transmembrane glycoprotein that acts as an accessory-signaling component of the B-cell antigen receptor (BCR). Recent evidence indicating the role of CD22 as a negative regulator of BCR signal transduction prompted us to test the possibility that genetic variations of human CD22 may be associated with autoimmune diseases. In this study, variation screening of the entire CD22 coding region was performed, and possible association with rheumatic diseases was tested, using the genomic DNA from 207 healthy Japanese individuals, 68 patients with systemic lupus erythematosus (SLE), and 119 patients with rheumatoid arthritis (RA). Through the variation screening, seven non-synonymous and four synonymous substitutions were identified. In addition, single base substitutions were found in two introns flanking exon-intron junctions. Among these variations, Q152E substitution within the second extracellular domain was observed with a marginally higher frequency in the patients with SLE (3/68, 4.4%) than that in healthy individuals (1/207, 0.5%) (P=0.048. SLE vs healthy individuals), although this difference was no longer significant after correction for the number of comparisons (Pc=0.62). No significant association was observed between any of the variations and RA. These findings indicate that a number of genetic variants are present in CD22, and suggest that CD22 could be considered a candidate for the susceptibility genes to autoimmune diseases.


An assessment of the limits of detection, sensitivity and specificity of three devices for public health-based drug checking of fentanyl in street-acquired samples.
Fentanyl has caused rapid increases in US and Canadian overdose deaths, yet its presence in illicit drugs is often unknown to consumers. This study examined the validity in identifying the presence of fentanyl of three portable devices that could be used in providing drug checking services and drug supply surveillance: fentanyl test strips, a hand-held Raman Spectrometer, and a desktop Fourier-Transform Infrared Spectrometer. In Fall 2017, we first undertook an assessment of the limits of detection for fentanyl, then tested the three devices' sensitivity and specificity in distinguishing fentanyl in street-acquired drug samples. Utilizing test replicates of standard fentanyl reference material over a range of increasingly lower concentrations, we determined the lowest concentration reliably detected. To establish the sensitivity and specificity for fentanyl, 210 samples (106 fentanyl-positive, 104 fentanyl-negative) previously submitted by law enforcement entities to forensic laboratories in Baltimore, Maryland, and Providence, Rhode Island, were tested using the devices. All sample testing followed parallel and standardized protocols in the two labs. The lowest limit of detection (0.100 mcg/mL), false negative (3.7%), and false positive rate (9.6%) was found for fentanyl test strips, which also correctly detected two fentanyl analogs (acetyl fentanyl and furanyl fentanyl) alone or in the presence of another drug, in both powder and pill forms. While less sensitive and specific for fentanyl, the other devices conveyed additional relevant information including the percentage of fentanyl and presence of cutting agents and other drugs. Devices for fentanyl drug checking are available and valid. Drug checking services and drug supply surveillance should be considered and researched as part of public health responses to the opioid overdose crisis.


Drying of polyacrylamide composite gels formed with various kappa- carrageenan content.
Drying of polyacrylamide (PAAm)-κ-carrageenan (κC) composite gels were monitored by using steady-state fluorescence technique. Disc shaped gels were formed from acrylamide (AAm) and N, N'- methylenebisacrylamide(Bis) with various κ- carrageenan (κC) contents by free radical crosslinking copolymerization in water. Pyranine (P) was doped as a fluorescence probe, and scattered light, I (sc), and fluorescence intensities, I, were monitored during drying of these gels. It is observed that fluorescence intensity of pyranine increased as drying time is increased for all samples. The increase in I was modeled using Stern- Volmer equation and diffusion with moving boundary. It is found that desorption coefficient, D decreased as κC contents were increased. Supporting gravimetrical and volumetric experiments were also carried out during drying of PAAm- κC composite gels.


Towards molecular movies with X-ray photon correlation spectroscopy.
In this perspective article we highlight research opportunities and challenges in probing structural dynamics of molecular systems using X-ray Photon Correlation Spectroscopy (XPCS). The development of new X-ray sources, such as 4th generation storage rings and X-ray free-electron lasers (XFELs), provides promising new insights into molecular motion. Employing XPCS at these sources allows to capture a very broad range of timescales and lengthscales, spanning from femtoseconds to minutes and atomic scales to the mesoscale. Here, we discuss the scientific questions that can be addressed with these novel tools for two prominent examples: the dynamics of proteins in biomolecular condensates and the dynamics of supercooled water. Finally, we provide practical tips for designing and estimating feasibility of XPCS experiments as well as on detecting and mitigating radiation damage.


Time-to-event analysis for sports injury research part 2: time-varying outcomes.
Time-to-event modelling is underutilised in sports injury research. Still, sports injury researchers have been encouraged to consider time-to-event analyses as a powerful alternative to other statistical methods. Therefore, it is important to shed light on statistical approaches suitable for analysing training load related key-questions within the sports injury domain. In the present article, we illuminate: (i) the possibilities of including time-varying outcomes in time-to-event analyses, (ii) how to deal with a situation where different types of sports injuries are included in the analyses (ie, competing risks), and (iii) how to deal with the situation where multiple subsequent injuries occur in the same athlete. Time-to-event analyses can handle time-varying outcomes, competing risk and multiple subsequent injuries. Although powerful, time-to-event has important requirements: researchers are encouraged to carefully consider prior to any data collection that five injuries per exposure state or transition is needed to avoid conducting statistical analyses on time-to-event data leading to biased results. This requirement becomes particularly difficult to accommodate when a stratified analysis is required as the number of variables increases exponentially for each additional strata included. In future sports injury research, we need stratified analyses if the target of our research is to respond to the question: 'how much change in training load is too much before injury is sustained, among athletes with different characteristics?' Responding to this question using multiple time-varying exposures (and outcomes) requires millions of injuries. This should not be a barrier for future research, but collaborations across borders to collecting the amount of data needed seems to be an important step forward.


The conversion of active to latent plasminogen activator inhibitor-1 is an energetically silent event.
PAI-1 is a proteinase inhibitor, which plays a key role in the regulation of fibrinolysis. It belongs to the serpins, a family of proteins that behave either as proteinase inhibitors or proteinase substrates, both reactions involving limited proteolysis of the reactive center loop and insertion of part of this loop into beta-sheet A. Titration calorimetry shows that the inhibition of tissue-type plasminogen and pancreatic trypsin are exothermic reactions with DeltaH = -20.3, and -22.5 kcal.mol(-1), respectively. The Pseudomonas aeruginosa elastase-catalyzed reactive center loop cleavage and inactivation of the inhibitor is also exothermic (DeltaH = -38.9 kcal.mol(-1)). The bacterial elastase also hydrolyses peptide-bound PAI-1 in which acetyl-TVASSSTA, the octapeptide corresponding to the P(14)-P(7) sequence of the reactive center loop is inserted into beta-sheet A of the serpin with DeltaH = -4.0 kcal.mol(-1). In contrast, DeltaH = 0 for the spontaneous conversion of the metastable active PAI-1 molecule into its thermodynamically stable inactive (latent) conformer although this conversion also involves loop/sheet insertion. We conclude that the active to latent transition of PAI-1 is an entirely entropy-driven phenomenon.


Relation of protein synthesis and transglutaminase activity to formation of the cross-linked envelope during terminal differentiation of the cultured human epidermal keratinocyte.
When serially cultivated human epidermal keratinocytes are placed in suspension culture they stop growing and form, beneath the plasma membrane, an insoluble envelope consisting of protein cross-linked by epsilon- (gamma-glutamyl)lysine. The formation of envelopes in suspended cells is preceded by a sharp decline in the rate of protein synthesis, and most envelopes appear only after the average rate of protein synthesis has fallen to a very low level. If protein synthesis is reduced over 98 percent with cycloheximide or emetine at the time that surface-grown cells are placed in suspension culture, cross-linked envelopes form in most of the cells. This shows that the precursor of the envelope and the cross-linking enzyme are already in the cytoplasm in most cells of growing surface cultures. The process of envelope formation by suspension cultures is actually accelerated by the inhibitors of protein synthesis; an increased number of cells with cross-linked envelopes is observable within 4-6 h after the addition of cycloheximide. The inhibitor also induces a large fraction of the cells of surface cultures to form enveloped within a few days. These findings suggest that arrest of protein synthesis leads to activation of the cross-linking process. Agents known to inhibit transglutaminase-mediated protein cross-linking-putrescine, iodoacetamide, and ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetate (EGTA)- also prevent envelope formation. Though the activity of the cross-linking transglutaminase depends on the presence of cellular Ca++, we have not been able to activate the cross-linking process by high external Ca++ concentration or ionophores.


Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia.
DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m(2)/day for 5 days (3.0 mg/m(2)/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m(2)/day for 5 days, two of three treated at 1.2 mg/m(2)/day for 5 days, and one of six treated at 0.9 mg/m(2)/day for 7 days. The recommended Phase II dose was 0.9 mg/m(2)/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.


Tuning out disorder-induced localization in nanophotonic cavity arrays.
Weakly coupled high-Q nanophotonic cavities are building blocks of slow-light waveguides and other nanophotonic devices. Their functionality critically depends on tuning as resonance frequencies should stay within the bandwidth of the device. Unavoidable disorder leads to random frequency shifts which cause localization of the light in single cavities. We present a new method to finely tune individual resonances of light in a system of coupled nanocavities. We use holographic laser-induced heating and address thermal crosstalk between nanocavities using a response matrix approach. As a main result we observe a simultaneous anticrossing of 3 nanophotonic resonances, which were initially split by disorder.


Changes in species diversity and size composition in the Firth of Clyde demersal fish community (1927-2009).
Following the repeal in 1962 of a long-standing ban on trawling, yields of demersal fish from the Firth of Clyde, southwest Scotland, increased to a maximum in 1973 and then declined until the directed fishery effectively ceased in the early 2000s. Since then, the only landings of demersal fish from the Firth have been by-catch in the Norway lobster fishery. We analysed changes in biomass density, species diversity and length structure of the demersal fish community between 1927 and 2009 from scientific trawl surveys, and related these to the fishery harvesting rate. As yields collapsed, the community transformed from a state in which biomass was distributed across numerous species (high species evenness) and large maximum length taxa were common, to one in which 90 per cent of the biomass was vested in one species (whiting), and both large individuals and large maximum length species were rare. Species evenness recovered quickly once the directed fishery ceased, but 10 years later, the community was still deficient in large individuals. The changes partly reflected events at a larger regional scale but were more extreme. The lag in response with respect to fishing has implications for attempts at managing a restoration of the ecosystem.


Detection of antibodies against Paracoccidioides brasiliensis melanin in in vitro and in vivo studies during infection.
Several cell wall constituents, including melanins or melanin-like compounds, have been implicated in the pathogenesis of a wide variety of microbial diseases caused by diverse species of pathogenic bacteria, fungi, and helminthes. Among these microorganisms, the dimorphic fungal pathogen Paracoccidioides brasiliensis produces melanin in its conidial and yeast forms. In the present study, melanin particles from P. brasiliensis were injected into BALB/c mice in order to produce monoclonal antibodies (MAbs). We identified five immunoglobulin G1 (IgG1) κ-chain and four IgM melanin-binding MAbs. The five IgG1 κ-chain isotypes are the first melanin-binding IgG MAbs ever reported. The nine MAbs labeled P. brasiliensis conidia and yeast cells both in vitro and in pulmonary tissues. The MAbs cross-reacted with melanin-like purified particles from other fungi and also with commercial melanins, such as synthetic and Sepia officinalis melanin. Melanization during paracoccidioidomycosis (PCM) was also further supported by the detection of IgG antibodies reactive to melanin from P. brasiliensis conidia and yeast in sera and bronchoalveolar lavage fluids from P. brasiliensis-infected mice, as well as in sera from human patients with PCM. Serum specimens from patients with other mycoses were also tested for melanin-binding antibodies by enzyme-linked immunosorbent assay, and cross-reactivities were detected for melanin particles from different fungal sources. These results suggest that melanin from P. brasiliensis is an immunologically active fungal structure that activates a strong IgG humoral response in humans and mice.


Overexpression of yeast spermidine synthase impacts ripening, senescence and decay symptoms in tomato.
Polyamines (PAs) are ubiquitous, polycationic biogenic amines that are implicated in many biological processes, including plant growth and development, but their precise roles remain to be determined. Most of the previous studies have involved three biogenic amines: putrescine (Put), spermidine (Spd) and spermine (Spm), and their derivatives. We have expressed a yeast spermidine synthase (ySpdSyn) gene under constitutive (CaMV35S) and fruit-ripening specific (E8) promoters in Solanum lycopersicum (tomato), and determined alterations in tomato vegetative and fruit physiology in transformed lines compared with the control. Constitutive expression of ySpdSyn enhanced intracellular levels of Spd in the leaf, and transiently during fruit development, whereas E8-ySpdSyn expression led to Spd accumulation early and transiently during fruit ripening. The ySpdSyn transgenic fruits had a longer shelf life, reduced shriveling and delayed decay symptom development in comparison with the wild-type (WT) fruits. An increase in shelf life of ySpdSyn transgenic fruits was not facilitated by changes in the rate of water loss or ethylene evolution. Additionally, the expression of several cell wall and membrane degradation-related genes in ySpdSyn transgenic fruits was not correlated with an extension of shelf life, indicating that the Spd-mediated increase in fruit shelf life is independent of the above factors. Crop maturity, indicated by the percentage of ripening fruits on the vine, was delayed in a CaMV35S-ySpdSyn genotype, with fruits accumulating higher levels of the antioxidant lycopene. Notably, whole-plant senescence in the transgenic plants was also delayed compared with WT plants. Together, these results provide evidence for a role of PAs, particularly Spd, in increasing fruit shelf life, probably by reducing post-harvest senescence and decay.


Memory for the search path: evidence for a high-capacity representation of search history.
Using a gaze-contingent paradigm, we directly measured observers' memory capacity for fixated distractor locations during search. After approximately half of the search objects had been fixated, they were masked and a spatial probe appeared at either a previously fixated location or a non-fixated location; observers then rated their confidence that the target had appeared at the probed location. Observers were able to differentiate the 12 most recently fixated distractor locations from non-fixated locations, but analyses revealed that these locations were represented fairly coarsely. We conclude that there exists a high-capacity, but low-resolution, memory for a search path.


Progesterone-mediated regulation of catechol-O-methyl transferase expression in endometrial cancer cells.
The effects of estrogen and progesterone on the expression of estrogen-metabolizing enzymes such as catechol-O-methyl transferase (COMT) are not known. COMT converts genotoxic catecholestrogens to anticarcinogenic methoxyestrogens in the endometrium. The aim of this study is to investigate the effect of progesterone on COMT expression in well-differentiated endometrial cancer cells. The wild-type Ishikawa cell line as well as progesterone receptor A- or progesterone receptor B-transfected Ishikawa cells were used for in vitro studies. The regulation of COMT expression by progesterone was studied using Western blots, Hoechst dye DNA proliferation studies, and wild-type and/or site-directed mutagenesis of COMT promoter 1-luciferase reporter gene. Progesterone upregulated COMT protein expression in Ishikawa cells through progesterone receptor A isoform. COMT promoter activity was differentially regulated by the 3 half-site progesterone response elements in the COMT promoter. High doses of 2-ME2 inhibited Ishikawa cell proliferation. These data suggest that COMT expression is hormonally regulated in well-differentiated human endometrial cancer cells. COMT regulation and 2-ME2 production in the endometrium may affect endometrial carcinogenesis.


Chemometric tools for identification of volatile aroma-active compounds in oregano.
One of the purposes of chemical analysis is to find quick and efficient methods to answer complex analytical questions in the life sciences. New analytical methods, in particular, produce a flood of data which are often very badly arranged. An effective way to overcome this problem is to apply chemometric methods. As part of the following investigations, three brands of oregano were analysed to identify their volatile aroma-active compounds. Two techniques were applied--gas chromatograpy-olfactometry (GC-O) and human sensory evaluation. Aroma-impact compounds could be identified in the main brands of oregano with the aid of chemometric methods (principal-components analysis, hierarchical cluster analysis, linear discriminant analysis, partial least-squares regression). Therefore, it is possible to reduce the analysis of sensory and olfactometry to relevant attributes. This makes classifying new species easier, much faster, and less expensive and is the premise for quick and more economic identification of new potential genotypes for oregano plant breeding. A comprehensive list of oregano key odourants, determined by GC-O and human sensory evaluation using different methods of supervised and unsupervised pattern cognition, has not previously been published.


Soyabean response to rhizobium inoculation across sub-Saharan Africa: Patterns of variation and the role of promiscuity.
Improving bacterial nitrogen fixation in grain legumes is central to sustainable intensification of agriculture in sub-Saharan Africa. In the case of soyabean, two main approaches have been pursued: first, promiscuous varieties were developed to form effective symbiosis with locally abundant nitrogen fixing bacteria. Second, inoculation with elite bacterial strains is being promoted. Analyses of the success of these approaches in tropical smallholder systems are scarce. It is unclear how current promiscuous and non-promiscuous soyabean varieties perform in inoculated and uninoculated fields, and the extent of variation in inoculation response across regions and environmental conditions remains to be determined. We present an analysis of on-farm yields and inoculation responses across ten countries in Sub Saharan Africa, including both promiscuous and non-promiscuous varieties. By combining data from a core set of replicated on-farm trials with that from a large number of farmer-managed try-outs, we study the potential for inoculation to increase yields in both variety types and evaluate the magnitude and variability of response. Average yields were estimated to be 1343 and 1227 kg/ha with and without inoculation respectively. Inoculation response varied widely between trials and locations, with no clear spatial patterns at larger scales and without evidence that this variation could be explained by yield constraints or environmental conditions. On average, specific varieties had similar uninoculated yields, while responding more strongly to inoculation. Side-by side comparisons revealed that stronger responses were observed at sites where promiscuous varieties had superior uninoculated yields, suggesting the availability of compatible, effective bacteria as a yield limiting factor and as a determinant of the magnitude of inoculation response.


Characterization of aortic root atherosclerosis in ApoE knockout mice: high-resolution in vivo and ex vivo MRM with histological correlation.
In vivo, cardiac-gated, black-blood, and ex vivo magnetic resonance microscopy (MRM) images of the aortic root, and histopathology data were obtained from 12 transgenic and wild-type (WT) mice. MRM was performed using a black-blood imaging spin-echo sequence with upstream and downstream in-flow saturation pulses to obtain aortic root images in three contrast techniques: proton density-weighted (PDW), T(1)- (T(1)W), and T(2)-weighted (T(2)W). Aortic wall thickness and area were measured and correlated with histopathology data (R > 0.90). Ex vivo lesion components (lipid core, fibrous tissue, and cell tissue) were identified and characterized by differing image contrast in PDW, T(1)W, and T(2)W MRM, and by histopathology. The differences between WT and transgenic mice for maximal wall thickness and area were statistically significant (P < 0.05). This study demonstrates the feasibility of in vivo murine aortic root lesion assessment and ex vivo plaque characterization by MRM.


Shedding light on Salmonella carriers.
Host-to-host transmission in most Salmonella serovars occurs primarily via the fecal-oral route. Salmonella enterica serovar Typhi is a human host-adapted pathogen and some S. Typhi patients become asymptomatic carriers. These individuals excrete large numbers of the bacteria in their feces and transmit the pathogen by contaminating water or food sources. The carrier state has also been described in livestock animals and is responsible for food-borne epidemics. Identification and treatment of carriers are crucial for the control of disease outbreaks. In this review, we describe recent advances in molecular profiling of human carriers and the use of animal models to identify potential host and bacterial genes involved in the establishment of the carrier state.


Effects of methionine containing paracetamol formulation on serum vitamins and trace elements in male rats.
Methionine is an effective antidote in the treatment of paracetamol-induced toxicity but at large doses it has been reported to induce or aggravate a number of pathological conditions. It also alters plasma levels of many vital elements and molecules. This study was designed to identify if the alteration observed for antioxidant vitamins and minerals especially at sub-toxic and toxic levels of exposure in our earlier study of 24-hour exposure period may warrant trace elements supplementation. This was investigated by carrying out a 48-hour study to test the ability of a living organism to restore homeostasis of these vital molecules and elements. The levels of antioxidant minerals and vitamins were estimated in the serum samples obtained from adult male Wistar rats exposed to paracetamol tablets. At 100 mg\kg BW (body weight) vitamin A, niacin, riboflavin, selenium and manganese were not significantly different from the control group. Moreover at 350 mg\kg, all these indices except zinc were not significantly different in the exposed group compared with controls whereas at 1000 mg\kg level of exposure manganese, selenium and vitamin E were not significantly decreased at the end of 48 hours of exposure but copper, niacin and vitamin A were significantly increased in the exposed group compared with the controls. These results suggest that with time the body may be capable of bringing about restoration of the levels of some of these elements\vitamins. This was more evident at 350 mg\kg level of exposure than a higher dose of 1000 mg\kg level.


Advanced Glycation End Products Are Associated With Physical Activity and Physical Functioning in the Older Population.
Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as advanced glycation end products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants. Cross-sectional data of 5,624 participants aged 65 years and older from the LifeLines Cohort Study were used. Linear regression analyses were utilized to study the associations between skin autofluorescence/AGE levels (AGE Reader), the number of physically active days (SQUASH), and physical functioning (RAND-36). A logistic regression analysis was used to study the associations between AGE levels and the compliance with the Dutch physical activity guidelines (SQUASH). A statistical significant association between AGE levels and the number of physically active days (β = -0.21, 95% confidence interval: -0.35 to -0.07, p = .004), physical functioning (β = -1.60, 95% confidence interval: -2.64 to -0.54, p = .003), and compliance with the Dutch physical activity guidelines (odds ratio = 0.76, 95% confidence interval: 0.62 to 0.94, p = .010) was revealed. This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population.


O-Antigen-Dependent Colicin Insensitivity of Uropathogenic Escherichia coli.
The outer membrane of Gram-negative bacteria presents a significant barrier for molecules entering the cell. Nevertheless, colicins, which are antimicrobial proteins secreted by Escherichia coli, can target other E. coli cells by binding to cell surface receptor proteins and activating their import, resulting in cell death. Previous studies have documented high rates of nonspecific resistance (insensitivity) of various E. coli strains toward colicins that is independent of colicin-specific immunity and is instead associated with lipopolysaccharide (LPS) in the outer membrane. This observation poses a contradiction: why do E. coli strains have colicin-expressing plasmids, which are energetically costly to retain, if cells around them are likely to be naturally insensitive to the colicin they produce? Here, using a combination of transposon sequencing and phenotypic microarrays, we show that colicin insensitivity of uropathogenic E. coli sequence type 131 (ST131) is dependent on the production of its O-antigen but that minor changes in growth conditions render the organism sensitive toward colicins. The reintroduction of O-antigen into E. coli K-12 demonstrated that it is the density of O-antigen that is the dominant factor governing colicin insensitivity. We also show, by microscopy of fluorescently labelled colicins, that growth conditions affect the degree of occlusion by O-antigen of outer membrane receptors but not the clustered organization of receptors. The result of our study demonstrate that environmental conditions play a critical role in sensitizing E. coli toward colicins and that O-antigen in LPS is central to this role.IMPORTANCEEscherichia coli infections can be a major health burden, especially with the organism becoming increasingly resistant to "last-resort" antibiotics such as carbapenems. Although colicins are potent narrow-spectrum antimicrobials with potential as future antibiotics, high levels of naturally occurring colicin insensitivity have been documented which could limit their efficacy. We identify O-antigen-dependent colicin insensitivity in a clinically relevant uropathogenic E. coli strain and show that this insensitivity can be circumvented by minor changes to growth conditions. The results of our study suggest that colicin insensitivity among E. coli organisms has been greatly overestimated, and as a consequence, colicins could in fact be effective species-specific antimicrobials targeting pathogenic E. coli such as uropathogenic E. coli (UPEC).


Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients.
Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised individuals. The epidemiology and pathogenesis of this infection are poorly understood, and the exact mode of transmission remains unclear. Recent studies reported clusters of PCP among immunocompromised patients, raising the suspicion of interhuman transmission. An unexpected increase of the incidence of PCP cases in our nephrology outpatient clinic prompted us to conduct a detailed analysis. Genotyping of 7 available specimens obtained from renal transplant recipients was performed using multi-locus DNA sequence typing (MLST). Fragments of 4 variable regions of the P. jirovecii genome (ITS1, 26S, mt26S, beta-tubulin) were sequenced and compared with those of 4 independent control patients. MLST analysis revealed identical sequences of the 4 regions among all 7 renal allograft recipients with available samples, indicating an infection with the same P. jirovecii genotype. We observed that all but 1 of the 19 PCP-infected transplant recipients had at least 1 concomitant visit with another PCP-infected patient within a common waiting area. This study provides evidence that nosocomial transmission among immunocompromised patients may have occurred in our nephrology outpatient clinic. Our findings have epidemiological implications and suggest that prolonged chemoprophylaxis for PCP may be warranted in an era of more intense immunosuppression.


Subconjunctival hemorrhages: presenting sign for hereditary hemochromatosis.
Hereditary hemochromatosis (HH) is a common hereditary disorder that primarily afflicts patients of Northern European descent. A single mutation of the HFE gene results in unregulated dietary iron uptake with the potential to deleteriously affect multiple organ systems including the eye. If HH is suspected, a screening test measuring transferrin saturation is initially obtained. Confirmation of this disorder is accomplished with genetic testing and liver biopsy. Treatment should commence immediately and undergo venesection (phlebotomy) treatments 2 to 4 times a year for the remainder of the patient's life. The following is a case of a 54-year-old male of Scottish-German descent who was evaluated for a subconjunctival hemorrhage (SCH). A review of the patient's record disclosed that he had 12 previous episodes of SCH over a 10-year period. He was undergoing a comprehensive evaluation for HH due to the recent diagnosis of this condition in his older brother. Hematologic analysis showed that our patient had a serum ferritin level 4 to 5 times higher than normal (1340 μg/L) and a homozygous recessive profile of the HFE gene. Once under maintenance venesection therapy, the frequency of the SCH diminished. HH must be considered a differential diagnosis in cases of recurrent SCH. Coupled with the recognition of characteristic physical signs and symptoms of HH, hematologic analysis and genetic testing may further aid in diagnosis. With early detection and treatment, the optometrist can make a significant impact on the life expectancy of the patient.


Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6.
The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration. Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib. Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model. Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.


Impact of oesophagitis classification in evaluating healing of erosive oesophagitis after therapy with proton pump inhibitors: a pooled analysis.
The results of clinical trials with proton pump inhibitors (PPIs) are usually based on the Hetzel-Dent (HD), Savary-Miller (SM), or Los Angeles (LA) classifications to describe the severity and assess the healing of erosive oesophagitis. However, it is not known whether these classifications are comparable. The aim of this study was to review systematically the literature to compare the healing rates of erosive oesophagitis with PPIs in clinical trials assessed by the HD, SM, or LA classifications. A recursive, English language literature search in PubMed and Cochrane databases to December 2006 was performed. Double-blind randomized control trials comparing a PPI with another PPI, an H2-RA or placebo using endoscopic assessment of the healing of oesophagitis by the HD, SM or LA, or their modified classifications at 4 or 8 weeks, were included in the study. The healing rates on treatment with the same PPI(s), and same endoscopic grade(s) were pooled and compared between different classifications using Fisher's exact test or chi2 test where appropriate. Forty-seven studies from 965 potential citations met inclusion criteria. Seventy-eight PPI arms were identified, with 27 using HD, 29 using SM, and 22 using LA for five marketed PPIs. There was insufficient data for rabeprazole and esomeprazole (week 4 only) to compare because they were evaluated by only one classification. When data from all PPIs were pooled, regardless of baseline oesophagitis grades, the LA healing rate was significantly higher than SM and HD at both 4 and 8 weeks (74, 71, and 68% at 4 weeks and 89, 84, and 83% at 8 weeks, respectively). The distribution of different grades in study population was available only for pantoprazole where it was not significantly different between LA and SM subgroups. When analyzing data for PPI and dose, the LA classification showed a higher healing rate for omeprazole 20 mg/day and pantoprazole 40 mg/day (significant at 8 weeks), whereas healing by SM classification was significantly higher for omeprazole 40 mg/day (no data for LA) and lansoprazole 30 mg/day at 4 and 8 weeks. The healing rate by individual oesophagitis grade was not always available or robust enough for meaningful analysis. However, a difference between classifications remained. There is a significant, but not always consistent, difference in oesophagitis healing rates with the same PPI(s) reported by the LA, SM, or HD classifications. The possible difference between grading classifications should be considered when interpreting or comparing healing rates for oesophagitis from different studies.


Argument structure and the representation of abstract semantics.
According to the dual coding theory, differences in the ease of retrieval between concrete and abstract words are related to the exclusive dependence of abstract semantics on linguistic information. Argument structure can be considered a measure of the complexity of the linguistic contexts that accompany a verb. If the retrieval of abstract verbs relies more on the linguistic codes they are associated to, we could expect a larger effect of argument structure for the processing of abstract verbs. In this study, sets of length- and frequency-matched verbs including 40 intransitive verbs, 40 transitive verbs taking simple complements, and 40 transitive verbs taking sentential complements were presented in separate lexical and grammatical decision tasks. Half of the verbs were concrete and half were abstract. Similar results were obtained in the two tasks, with significant effects of imageability and transitivity. However, the interaction between these two variables was not significant. These results conflict with hypotheses assuming a stronger reliance of abstract semantics on linguistic codes. In contrast, our data are in line with theories that link the ease of retrieval with availability and robustness of semantic information.


Near-field microscopy: throwing light on the nanoworld.
Optical microscopy with nanoscale resolution, beyond that which is possible with conventional diffraction-limited microscopy, may be achieved by scanning a nanoantenna in close proximity to a sample surface. This review will first aim to provide an overview of the basic principles of this technique of scanning near-field optical microscopy (SNOM), before moving on to consider the most widely implemented form of this microscopy, in which the sample is illuminated through a small aperture held less than 10 nm from the sample surface for optical imaging with a resolution of ca. 50 nm. As an example of the application of this microscopy, the results of SNOM measurements of light-emitting polymer nanostructures are presented. In particular, SNOM enables the unambiguous identification of the different phases present in the nanostructures, through the local analysis of the fluorescence from the polymers. The exciting new possibilities for high-resolution optical microscopy and spectroscopy promised by apertureless SNOM techniques are also considered. Apertureless SNOM may involve local scattering of light from a sample surface by a tip, local enhancement of an optical signal by a metal tip, or the use of a fluorescent molecule or nanoparticle attached to a tip as a local optical probe of a surface. These new optical nanoprobes offer the promise of optical microscopy with true nanometre spatial resolution.


Ultrafast Excited-State Localization in Cs2AgBiBr6 Double Perovskite.
Cs2AgBiBr6 is a promising metal halide double perovskite offering the possibility of efficient photovoltaic devices based on lead-free materials. Here, we report on the evolution of photoexcited charge carriers in Cs2AgBiBr6 using a combination of temperature-dependent photoluminescence, absorption and optical pump-terahertz probe spectroscopy. We observe rapid decays in terahertz photoconductivity transients that reveal an ultrafast, barrier-free localization of free carriers on the time scale of 1.0 ps to an intrinsic small polaronic state. While the initially photogenerated delocalized charge carriers show bandlike transport, the self-trapped, small polaronic state exhibits temperature-activated mobilities, allowing the mobilities of both to still exceed 1 cm2 V-1 s-1 at room temperature. Self-trapped charge carriers subsequently diffuse to color centers, causing broad emission that is strongly red-shifted from a direct band edge whose band gap and associated exciton binding energy shrink with increasing temperature in a correlated manner. Overall, our observations suggest that strong electron-phonon coupling in this material induces rapid charge-carrier localization.


Illumina MiSeq sequencing analysis of fungal diversity in stored dates.
Date palm has been a major fruit tree in the Middle East over thousands of years, especially in the Arabian Peninsula. Dates are consumed fresh (Rutab) or after partial drying and storage (Tamar) during off-season. The aim of the study was to provide in-depth analysis of fungal communities associated with the skin (outer part) and mesocarp (inner fleshy part) of stored dates (Tamar) of two cultivars (Khenizi and Burny) through the use of Illumina MiSeq sequencing. The study revealed the dominance of Ascomycota (94%) in both cultivars, followed by Chytridiomycota (4%) and Zygomycota (2%). Among the classes recovered, Eurotiomycetes, Dothideomycetes, Saccharomycetes and Sordariomycetes were the most dominant. A total of 54 fungal species were detected, with species belonging to Penicillium, Alternaria, Cladosporium and Aspergillus comprising more than 60% of the fungal reads. Some potentially mycotoxin-producing fungi were detected in stored dates, including Aspergillus flavus, A. versicolor and Penicillium citrinum, but their relative abundance was very limited (<0.5%). PerMANOVA analysis revealed the presence of insignificant differences in fungal communities between date parts or date cultivars, indicating that fungal species associated with the skin may also be detected in the mesocarp. It also indicates the possible contamination of dates from different cultivars with similar fungal species, even though if they are obtained from different areas. The analysis shows the presence of different fungal species in dates. This appears to be the first study to report 25 new fungal species in Oman and 28 new fungal species from date fruits. The study discusses the sources of fungi on dates and the presence of potentially mycotoxin producing fungi on date skin and mesocarp.


Molecular modeling of two distinct triangular oligomers in amyloid beta-protein.
Amyloid-beta (Abeta) peptides exhibit many distinct structural morphology at the early aggregate stage, some of which are biological relevant to the pathogenesis of Alzheimer's disease (AD). Atomic-resolution structures of the early Abeta aggregates and their conformational changes in amyloid aggregation remain elusive. Here, we perform all-atom molecular modeling and dynamics simulations to obtain two stable triangular-like Abeta structures with the lowest packing energy, one corresponding to the Tycko's model (Paravastu, A.; Leapman, R.; Yau, W.; Tycko, R. Proc. Nat. Acad. Soc. U.S.A. 2008, 105, 18349-18354) (referred to C-WT model) and the other corresponding to computational model (N-WT model). Both models have the same 3-fold symmetry but distinct beta-sheet organizations in which three Abeta hexamers pack together via either C-terminal beta-strand residues or N-terminal beta-strand residues forming distinct hydrophobic cross section. Structural and energetic comparisons of two 3-fold Abeta oligomers, coupled with structural changes upon the mutations occurring at the interacting interfaces, reveal that although hydrophobic interactions are still dominant forces, electrostatic interactions are more favorable in the N-WT model due to the formation of more and stable intersheet salt bridges, while solvation energy is more favorable in the C-WT model due to more exposed hydrophilic residues to solvent. Both models display many common features similar to other amyloid oligomers and therefore are likely to be biologically relevant.


The reliability and validity of the physical activity questions in the WHO health behaviour in schoolchildren (HBSC) survey: a population study.
To assess the test-retest reliability and validity of the physical activity questions in the World Health Organisation health behaviour in schoolchildren (WHO HBSC) survey. In the validity study, the Multistage Fitness Test was administered to a random sample of year 8 (mean age 13.1 years; n = 1072) and year 10 (mean age 15.1 years; n = 954) high school students from New South Wales (Australia) during February/March 1997. The students completed the self report instruments on the same day. An independent sample of year 8 (n = 121) and year 10 (n = 105) students was used in the reliability study. The questionnaire was administered to the same students on two occasions, two weeks apart, and test-retest reliability was assessed. Students were classified as either active or inadequately active on their combined responses to the questionnaire items. Kappa and percentage agreement were assessed for the questionnaire items and for a two category summary measure. All groups of students (boys and girls in year 8 and year 10) classified as active (regardless of the measure) had significantly higher aerobic fitness than students classified as inadequately active. As a result of highly skewed binomial distributions, values of kappa were much lower than percentage agreement for test-retest reliability of the summary measure. For year 8 boys and girls, percentage agreement was 67% and 70% respectively, and for year 10 boys and girls percentage agreement was 85% and 70% respectively. These brief self report questions on participation in vigorous intensity physical activity appear to have acceptable reliability and validity. These instruments need to be tested in other cultures to ensure that the findings are not specific to Australian students. Further refinement of the measures should be considered.


Longitudinal Changes in Measured Glomerular Filtration Rate, Renal Fibrosis and Biomarkers in a Rat Model of Type 2 Diabetic Nephropathy.
Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes. Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats. Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression.


Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022.
Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. To present the voting results of the APCCC 2022. The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.


Glycogen pseudoground glass change in hepatocytes.
Ground glass cytoplasmic change in hepatocytes is typically associated with chronic hepatitis B infection. We report 12 cases of glycogen pseudoground glass change that closely mimics hepatitis B inclusions. Nine individuals were immunosuppressed secondary to liver or kidney transplant (N=3), bone marrow transplant (N=2), HIV infection (N=2), kidney dialysis (N=1), or chronic inflammatory bowel disease (N=1). Medication history was available in 10 individuals and all were on multiple medications (range 2 to 33). Histologically, the pseudoground glass change was identical to the ground glass change seen in chronic hepatitis B infection, with distinct, circumscribed, gray-glassy inclusions surrounded by a rim of cytoplasm. The background livers showed mild or no inflammation and mild or no fibrosis. All cases were negative for chronic hepatitis B infection. The pseudoground glass change was PAS positive and diastase sensitive. Electron microscopy of the inclusions showed glycogen in 3/3 cases. No evidence for viral particles or significant endoplasmic reticulum proliferation was seen. Three cases had follow-up biopsies (1, 1, and 36 mo), and the pseudoground glass was persistent in 2 cases and showed partial resolution in 1 case (1 mo biopsy interval). We conclude that glycogen pseudoground glass change is typically seen in immunosuppressed individuals on numerous medications. The changes are generally seen in the background of mild chronic hepatitis with mild or no fibrosis. Glycogen pseudoground glass change can resolve, but may also persist for years.


Imputation of individual cancer cases to occupational causes.
Many potential occupational causes of cancer have been documented. Imputation of an individual cancer to occupational or other causes is, however, difficult. A method based on the Bayes theorem is proposed for assessing causal relationships at the individual level. Causality assessment, dealing with four types of persons defined by exposure and the occurrence of cancer, was linked with imputation, only dealing with persons who have cancer and were exposed. Imputation was then formulated using the Bayes theorem, relating epidemiologic information regarding causes, a patient's exposure history, and the posterior odds that the cancer was caused by a suspected occupational exposure. Data needed to apply a Bayesian method were defined in terms of relative risks, proportion of people exposed in populations, and the frequency of a positive relevant characteristic for persons without cancer. A relevant characteristic was defined using a formal consensus between experts. The method was then illustrated with cases of mesothelioma and lung cancer in possible relation to asbestos. Experts defined the relevant characteristics as being qualification of occupational exposure, intensity of exposure, latency, disease characteristics, and presence of causal agent in the body. Application to mesothelioma and lung cancer cases illustrated the potential usefulness of the method. The importance of occupational exposure in the formulation of imputation underscores the need for available and reliable data sources on occupational exposures. The proposed method could become a powerful tool for the expert assessment of causes of cancer cases, provided data become available in individual files and the literature.


Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial.
To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder. In this 12-week, randomized, double-blind, placebo-controlled trial, adults with bipolar I disorder (DSM-IV criteria) experiencing a manic or mixed episode with a Young Mania Rating Scale (YMRS) score of >or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo. Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks. The study was conducted from October 2001 through October 2003. The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase. The mean +/- SD change in YMRS score from baseline was -10.1 +/- 8.7 (-40.1%) in the topiramate group (N = 143) and -9.6 +/- 8.2 (-40.2%) in the placebo group (N = 144, p = .797). Greater than 50% reduction in YMRS was achieved by 39% of the topiramate group and 38% of the placebo group (p = .914). No significant treatment differences were observed for secondary efficacy measures. Compared with adjunctive placebo, adjunctive topiramate did not worsen mania or induce depression. Paresthesia, diarrhea, and anorexia were more common in the topiramate group. The topiramate group achieved greater reductions than the placebo group in body weight (-2.5 vs. 0.2 kg, p < .001) and body mass index (-0.84 vs. 0.07 kg/m(2), p < .001). In patients treated with lithium or valproate, there was no difference in the reduction of YMRS score in the topiramate and placebo groups. Both groups showed declines of 40%. Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms.


Aortic hypertrophy and "waterlogging" in the development of coarctation hypertension.
To study the mechanisms and roles of vascular structural changes during the development of hypertension, we coarcted or sham-coarcted the abdominal aorta of rats. At intervals of 3 to 56 days later, we obtained standardized segments of thoracic and abdominal aortas for measurement of dry weight, water content, and amino acid content. Carotid arterial pressure was elevated by day 5 in coarcted rats and remained elevated. Femoral and tail arterial pressures remained normal. Cardiac ventricular weight and dry weight of the thoracic aorta, normalized for body weight, rose rapidly over 3-10 days in coarcted rats, remaining constant at 50-60% above levels in sham-coarcted rats thereafter. In contrast, water content of thoracic aorta in coarcted rats peaked at 123% of control values on day 7 (p less than 0.001), falling rapidly thereafter to levels about half of peak. Increments in dry weight and water content of the normotensive abdominal aortic segments were of far lesser magnitude and occurred 1 to 2 weeks later, probably reflecting the effects of initial hypotension of the hindquarters. Percent hydroxyproline of intima-media segments of the thoracic aorta remained normal during the 8-week period, indicating that increases in aortic dry weight did not represent disproportional fibrosis and thus are attributable to muscular hypertrophy. These results provide support for the hypothesis that arterial wall "waterlogging" is primarily an early manifestation of the hypertensive process. The greatest magnitude of waterlogging coincides with the rapid early increase in aortic dry weight, representing hypertrophy, which suggests common mechanisms, such as activation of Na+-H+ antiport.


Cognitive outcomes after neonatal encephalopathy.
To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies. The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development-II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment-Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models. Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, -49.3 to -35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back ≥1 grade level. Cognitive impairment remains an important concern for all children with neonatal encephalopathy.


Cessation of injecting drug use: The effects of health service utilisation, drug use and demographic factors.
Injecting drug use is associated with a range of harms, however cessation of injecting is rare. There is a lack of evidence on factors associated with cessation, notably those related to health services other than drug treatment. We examined the incidence and identified longitudinal correlates of first episode of cessation in a cohort of people who inject drugs (PWID). Using discrete-time survival analysis, we examined correlates of the first episode of cessation (no self-reported injecting drug use in the past 12 months), including the use of health services, socio-demographics and drug-related behaviour in a cohort of PWID recruited between 2008 and 2010. The cohort of 467 participants contributed 1527 person-years from recruitment to 2014. Under a fifth (17.8%) of people reported cessation of 12 months or more, yielding a cessation rate of 5.4 events per 100 person-years. Younger age (25-29 compared to 30 and above) (adjusted hazard ratio (AHR) 1.79, 95% confidence interval (CI) 1.07-3.00) and male gender (AHR 1.67, 95% CI 2.01-2.76) were positively associated with cessation, while past year use of benzodiazepines (AHR 0.45, 95% CI 0.28-0.72), arrest in the past year (AHR 0.50, 95% CI 0.30-0.83) and low SF-8 physical dimension score (AHR 0.42, 95% CI 0.20-1.88) were negatively associated with cessation. Outpatient service use had the largest effect on cessation (AHR 2.28, 95% CI 0.94-5.48, p=0.067). Low rates of cessation emphasise the need for sustained and comprehensive harm reduction services. The relationship between outpatient services and cessation suggests that further research into the use in health services among PWID is warranted.


Adolescent Substance Use Prevention: Long-Term Benefits of School Engagement.
To determine if school engagement is a viable target for early prevention of adolescent substance use, this study investigated whether school engagement in early adolescence (ages 12-14) is a cause of alcohol and cannabis use during middle to late adolescence (ages 15-19). To facilitate causal inference, inverse probability of treatment weights (IPTWs), which are based on estimated probabilities of treatment selection (ie, school engagement), were created based on a robust set of potential confounders. Using the IPTWs, a cumulative link mixed model was fit to examine the impact of school engagement on alcohol and cannabis use among an ethnically diverse sample of adolescents (N = 360). School engagement was associated with a lower level of alcohol and cannabis use from age 15 to 18. School engagement was not associated with change in alcohol and cannabis use over time, suggesting that school engagement emits its effect early in the developmental course of substance use and offers protection throughout adolescence. This study supports a compensatory role of early school engagement in substance use across middle and late adolescence. School engagement is a malleable factor and thus offers an avenue for prevention efforts.


Family-centred interventions by primary healthcare services for Indigenous early childhood wellbeing in Australia, Canada, New Zealand and the United States: a systematic scoping review.
Primary healthcare services in Australia, Canada, New Zealand and the United States have embraced the concept of family-centred care as a promising approach to supporting and caring for the health of young Indigenous children and their families. This scoping review assesses the quality of the evidence base and identifies the published literature on family- centred interventions for Indigenous early childhood wellbeing. Fourteen electronic databases, grey literature sources and the reference lists of Indigenous maternal and child health reviews were searched to identify relevant publications from 2000 to 2015. Studies were included if the intervention was: 1) focussed on Indigenous children aged from conception to 5 years from the abovementioned countries; 2) led by a primary healthcare service; 3) described or evaluated; and 4) scored greater than 50% against a validated scale for family-centredness. The study characteristics were extracted and quality rated. Reported aims, strategies, enablers and outcomes of family-centredcare were identified using grounded theory methods. Eighteen studies (reported in 25 publications) were included. Three were randomised controlled studies; most were qualitative and exploratory in design. More than half of the publications were published from 2012 to 2015. The overarching aim of interventions was to promote healthy families. Six key strategies were to: support family behaviours and self- care, increase maternal knowledge, strengthen links with the clinic, build the Indigenous workforce, promote cultural/ community connectedness and advocate for social determinants of health. Four enablers were: competent and compassionate program deliverers, flexibility of access, continuity and integration of healthcare, and culturally supportive care. Health outcomes were reported for Indigenous children (nutritional status; emotional/behavioural; and prevention of injury and illness); parents/caregivers (depression and substance abuse; and parenting knowledge, confidence and skills); health services (satisfaction; access, utilization and cost) and community/cultural revitalisation. The evidence for family-centred interventions is in the early stages of development, but suggests promise for generating diverse healthcare outcomes for Indigenous children and their parents/caregivers, as well as satisfaction with and utilisation of healthcare, and community/cultural revitalisation. Further research pertaining to the role of fathers in family-centred care, and the effects and costs of interventions is needed.