OBJECTIVE

To better understand medical decision making in the context of "preference sensitive care," we investigated factors associated with breast cancer patients' satisfaction with the type of surgery received and with the decision process.

METHODS

For a population-based sample of recently diagnosed breast cancer patients in the Detroit and Los Angeles metropolitan areas (N=1,633), demographic and clinical data were obtained from the Surveillance, Epidemiology, and End Results tumor registry, and self-reported psychosocial and satisfaction data were obtained through a mailed survey (78.4 percent response rate).

METHODS

Cross-sectional design in which multivariable logistic regression was used to identify sociodemographic and clinical factors associated with three satisfaction measures: low satisfaction with surgery type, low satisfaction with the decision process, and decision regret.

RESULTS

Overall, there were high levels of satisfaction with both surgery and the decision process, and low rates of decision regret. Ethnic minority women and those with low incomes were more likely to have low satisfaction or decision regret. In addition, the match between patient preferences regarding decision involvement and their actual level of involvement was a strong indicator of satisfaction and decision regret/ambivalence. While having less involvement than preferred was a significant indicator of low satisfaction and regret, having more involvement than preferred was also a risk factor. Women who received mastectomy without reconstruction were more likely to report low satisfaction with surgery (odds ratio [OR]=1.54, p<.05), low satisfaction with the process (OR=1.37, p<.05), and decision regret (OR=1.55, p<.05) compared with those receiving breast conserving surgery (BCS). An additional finding was that as patients' level of involvement in the decision process increased, the rate of mastectomy also increased (p<.001).

CONCLUSIONS

A significant proportion of breast cancer patients experience a decision process that matches their preferences for participation, and report satisfaction with both the process and the outcome. However, women who report more involvement in the decision process are significantly less likely to receive a lumpectomy. Thus, increasing patient involvement in the decision process will not necessarily increase use of BCS or lead to greater satisfaction. The most salient aspect for satisfaction with the decision making process is the match between patients' preferences and experiences regarding participation.

Cancer stem cells (CSCs) sustain tumor growth through their ability to self-renew and to generate differentiated progeny. These functions endow CSCs with the potential to initiate secondary tumors bearing characteristics similar to those of the parent. Recently the hair follicle stem cell marker CD34 was used to purify a CSC-like cell population from early skin tumors arising from treatment with 7,12-dimethylbenz[α]anthracene/12-o-tetradecanoylphorbol-13-acetate, which typically generates benign papillomas that occasionally progress to squamous cell carcinomas (SCCs). In the present study, we identify and characterize CSCs purified from malignant SCCs. We show that SCCs contain two highly tumorigenic CSC populations that differ in CD34 levels but are enriched for integrins and coexist at the SCC-stroma interface. Intriguingly, whether CD34(lo) or CD34(hi), α6(hi)β1(hi) populations can initiate secondary tumors by serial limit-dilution transplantation assays, but α6(lo)β1(lo) populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34(lo) and CD34(hi) α6(hi)β1(hi)CSCs, indicating their nonhierarchical organization. Genomic profiling and hierarchical cluster analysis show that these two CSC subtypes share a molecular signature distinct from either the CD34(-) epidermal or the CD34(hi) hair follicle stem cell signature. Although closely related, α6(hi)β1(hi)CD34(lo) and α6(hi)β1(hi)CD34(hi) CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of α6(hi)β1(hi)CD34(hi) CSCs is sensitive to whether they can initiate a TGF-β receptor II-mediated response to counterbalance elevated focal adhesion kinase-mediated integrin signaling within the tumor. Overall, the coexistence and interconvertibility of CSCs with differing sensitivities to their microenvironment pose challenges and opportunities for SCC cancer therapies.

OBJECTIVE

To examine the frequency and reasons for rehospitalization in persons with acute traumatic spinal cord injury (SCI) during follow-up years and to examine the association between rehospitalization and demographics, neurologic category, payer sources, length of stay (LOS), discharge motor FIM instrument score, and discharge residence.

METHODS

Survey design with analysis of cross-sectional data.

METHODS

Model Spinal Cord Injury Systems (MSCIS) centers.

METHODS

Data for 8668 persons with SCI from 16 MSCIS centers entered in the National Spinal Cord Injury Statistical Center database between 1995 and 2002.

METHODS

Not applicable.

METHODS

MSCIS Forms I and II were used to identify the annual incidence, medical complications, and etiologies of rehospitalizations reported at 1-, 5-, 10-, 15-, and 20-year follow-ups.

RESULTS

The leading cause of rehospitalization was diseases of the genitourinary system, including urinary tract infections (UTIs). Diseases of the respiratory system tended to be more likely in patients with tetraplegia (C1-8 American Spinal Injury Association [ASIA] grades A, B, C); whereas patients with paraplegia (T1-S5 ASIA grades A, B, C) were more likely to be rehospitalized for pressure ulcers. The rate of rehospitalization was significantly higher at year 1, 5, and 20 for those who were discharged to a skilled nursing facility after acute rehabilitation. Lower motor score using the FIM was predictive of rehospitalization (P=.000). The average LOS per rehospitalization at the year-5 follow-up was approximately 12 days, which is lower than in past MSCIS reports.

CONCLUSIONS

Despite improvements in SCI medical management, rehospitalization rates remain high, with an increased incidence in conditions associated with the genitourinary system (including UTIs), respiratory complications (including pneumonia), and diseases of the skin (including pressure ulcers). Acutely injured patients need close follow-up to reduce morbidity and rehospitalizations.

Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) → PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.

During many acute viral and bacterial infections, IL-7 receptor alpha-chain (IL-7Ralpha) is expressed on a subset of effector CD8 T cells that preferentially develop into long-lived memory CD8 T cells. These cells functionally require IL-7Ralpha, but it is unclear whether IL-7Ralpha acts mainly to induce their differentiation into memory cells or to sustain their long-term survival. To examine this question, IL-7Ralpha was constitutively overexpressed on all antigen-specific effector CD8 T cells during viral infection. Constitutive IL-7Ralpha expression had minimal effects on the numbers or function of effector and memory CD8 T cells formed. This indicated that IL-7Ralpha expression is not sufficient to drive memory cell development. In particular, the forced IL-7Ralpha expression did not rescue the killer cell lectin-like receptor G1 (KLRG1)(hi) short-lived effector CD8 T cells from death, showing that the majority of effector CD8 T cells die in an IL-7Ralpha-independent manner. Moreover, we found that, regardless of the ectopic expression of IL-7Ralpha, the KLRG1(hi), but not the KLRG1(lo) effector CD8 T cells, were unable to proliferate well to IL-7, which may be due to increased amounts of p27(kip) in KLRG1(hi) cells. Because IL-7 can destabilize p27(kip), this result suggested that KLRG1(hi) and KLRG1(lo) effector CD8 T cells naturally differ in their ability to transmit IL-7 signals. Altogether, these results reveal that IL-7Ralpha expression is permissive, but not instructive, to the creation of memory CD8 T cells.

BACKGROUND

Vitamin D deficiency is associated with many adverse health outcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites.

OBJECTIVE

Our objective was to examine the relationship among three vitamin D-related genes and levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) and African Americans (AAs).

METHODS

The cross-sectional Insulin Resistance Atherosclerosis Family Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42 families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA), Texas (HAs; 504 individuals from 58 families).

METHODS

Plasma levels of 25(OH)D and 1,25(OH)2D were measured.

RESULTS

Levels of 25(OH)D were highest in SLV-HAs [18.3 +/- 7.7 ng/ml (45.7 +/- 19.2 nmol/liter)], lower in SA-HAs [14.6 +/- 6.4 ng/ml (36.4 +/- 16.0 nmol/liter)], and lowest in AAs [11.0 +/- 5.4 ng/ml (27.5 +/- 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5 +/- 13.9 pg/ml (113.1 +/- 36.1 pmol/liter)] and SLV-HAs [43.2 +/- 13.3 pg/ml (112.3 +/- 34.6 pmol/liter)], but higher in SA-HAs [48.6 +/- 17.0 pg/ml (126.4 +/- 44.2 pmol/liter)]. After adjusting for gender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D binding protein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588, was associated with 1,25(OH)2D at all three study centers.

CONCLUSIONS

SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin Resistance Atherosclerosis Family Study.

BACKGROUND

Residents in poor neighborhoods have higher body mass index (BMI) and eat less healthfully. One possible reason might be the quality of available foods in their area. Location of grocery stores where individuals shop and its association with BMI were examined.

METHODS

The 2000 U.S. Census data were linked with the Los Angeles Family and Neighborhood Study (L.A.FANS) database, which consists of 2620 adults sampled from 65 neighborhoods in Los Angeles County between 2000 and 2002. In 2005, multilevel linear regressions were used to estimate the associations between BMI and socioeconomic characteristics of grocery store locations after adjustment for individual-level factors and socioeconomic characteristics of residential neighborhoods.

RESULTS

Individuals have higher BMI if they reside in disadvantaged areas and in areas where the average person frequents grocery stores located in more disadvantaged neighborhoods. Those who own cars and travel farther to their grocery stores also have higher BMI. When controlling for grocery store census tract socioeconomic status (SES), the association between residential census tract SES and BMI becomes stronger.

CONCLUSIONS

Where people shop for groceries and distance traveled to grocery stores are independently associated with BMI. Exposure to grocery store mediates and suppresses the association of residential neighborhoods with BMI and could explain why previous studies may not have found robust associations between residential neighborhood predictors and BMI.

BACKGROUND

A high rate of low-income, ethnic minority women delay or fail to keep appointments following abnormal mammograms. This study was designed to test the effectiveness of a structured counseling and patient navigation intervention for improving follow-up rates at a large public sector medical center.

METHODS

This randomized clinical trial, conducted in Los Angeles 2001-2002, included 204 women with abnormal mammograms referred for follow-up who were then assigned to intervention or usual care. The primary outcome was the rate of follow-up through diagnostic resolution within eight months.

RESULTS

The intervention resulted in a significant increase in the rate of adherence to follow-up through diagnostic resolution. The intervention group was much more likely to be adherent through diagnostic resolution than the control group (90% vs. 66%, OR=4.48, p<0.001) and were more likely to experience timely adherence than UC patients (77% vs. 57%, OR=2.5, p=0.01). Intervention effectiveness was not significantly different for women assigned to different levels of service intensity.

CONCLUSIONS

Patient navigation and counseling driven by a structured clinical algorithm are highly effective strategies to improve diagnostic resolution follow-up among low-income, ethnic minority women with abnormal mammograms. The intervention algorithm and available training materials can be adapted for diverse care systems serving high-risk women to decrease loss to follow-up.

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.

We have used mouse mAbs, 3F11 and 06B4, that are specific for highly conserved epitopes of Neisseria gonorrhoeae lipooligosaccharides (LOS) to identify immunochemically similar structures on human erythrocytes. mAb 3F11 agglutinated erythrocytes from all randomly selected adult humans, while mAb 06B4 agglutinated only 80% of the same specimens. The antibodies had an activity with erythrocytes similar to human cold agglutinins in that agglutination occurred at 4 degrees C and decreased with increasing incubation temperature. Human infant erythrocytes were agglutinated less well, but enzymatic treatment of either infant or adult cells resulted in an increase in expression of the 3F11- and 06B4-defined epitopes. Both antibodies bound to a series of neutral glycosphingolipids from human erythrocytes and neutrophils that have a type 2 (Gal beta 1----4GlcNAc) or N-acetyllactosamine structure. Neither antibody bound to glycosphingolipids from human meconium, which have a type 1 (Gal beta 1----3GlcNAc) structure. The antibodies were unable to bind to N-acetyl-lactosamine glycosphingolipids with a nonreducing terminal sialic acid or a Gala1----3Gal disaccharide. Antibody binding also was blocked by the presence of fucose linked to the penultimate glucosamine residue of N-acetyllactosamine glycosphingolipids. Although both antibodies bound to linear and branched-chain N-acetyllactosamine glycosphingolipids, 3F11 had a higher affinity for branched structures than did 06B4. The activity of 3F11 with human adult and infant treated and untreated erythrocytes with N-acetyllactosamine glycosphingolipids, and with LOS was very similar, if not identical, in specificity to 1B2, an mAb prepared from mice inoculated with a linear N-acetyllactosamine glycosphingolipid.

BACKGROUND

Prescription opioids are the most frequently misused class of prescription drugs amongst young adults. Initiation into prescription opioid misuse is an important public health concern since opioids are increasingly associated with drug dependence and fatal overdose. Descriptive data about initiation into prescription opioid misuse amongst young injection drug users (IDUs) are scarce.

METHODS

An exploratory qualitative study was undertaken to describe patterns of initiation into prescription opioid misuse amongst IDUs aged 16-25 years. Those young IDUs who had misused a prescription drug at least three times in the past three months were recruited during 2008 and 2009 in Los Angeles (n=25) and New York (n=25). Informed by an ethno-epidemiological approach, descriptive data from a semi-structured interview guide were analysed both quantitatively and qualitatively.

RESULTS

Initiation into prescription opioid misuse was facilitated by easy access to opioids via participant's own prescription, family, or friends, and occurred earlier than misuse of other illicit drugs, such as heroin. Nearly all transitioned into sniffing opioids, most injected opioids, and many initiated injection drug use with an opioid. Motives for transitions to sniffing and injecting opioids included obtaining a more potent high and/or substituting for heroin; access to multiple sources of opioids was common amongst those who progressed to sniffing and injecting opioids.

CONCLUSIONS

Prescription opioid misuse was a key feature of trajectories into injection drug use and/or heroin use amongst this sample of young IDUs. A new pattern of drug use may be emerging whereby IDUs initiate prescription opioid misuse before using heroin.

The integrin alpha4beta7 binds to MAdCAM-1 and contributes to homing of lymphocytes to gut and other mucosal tissues. In humans, the alpha4beta7(hi) subset of circulating memory cells appears to have been primed in mucosal tissues. The factors that determine whether alpha4beta7(lo) naive cells become alpha4beta(hi) or alpha4beta7(-) cells upon differentiation are poorly understood but could include an influence of the activating antigen-presenting cell. To address this point, the induction of alpha4beta7 following activation of mouse cells with the APC-dependent stimulus soluble anti-CD3 has been examined. Almost all mouse T cells freshly isolated from mesenteric lymph nodes (MLN) and peripheral (PLN; axillary, brachial and inguinal) lymph nodes stained only weakly for alpha4beta7 but a subpopulation became alpha4beta7(hi) upon activation with anti-CD3 in a cell cycle- and accessory cell-dependent manner. A small proportion (approximately 1.5 %) of the starting cells gave rise to alpha4beta7(hi) cells after culture. A higher proportion of alpha4beta7(hi) cells were generated in MLN than PLN cultures. Peyer's patch cultures gave intermediate values. In crossover experiments, MLN dendritic cells (DC) induced higher proportions and numbers of alpha4beta7(hi) cells than PLN DC irrespective of the source of T cells. Therefore, in addition to their other immunoregulatory roles, DC have the potential to shape immune responses by influencing the homing of the lymphocytes they activate.

BACKGROUND

Several studies have investigated the possible role of the adjuvant chemotherapy after curative resection for gastric cancer failing to show a clear indication; previous meta-analyses suggested small survival benefit of adjuvant chemotherapy, but the statistical methods used were open to criticisms.

METHODS

Randomised trials were identified by means of Medline and CancerLit and by selecting references from relevant articles. Systematic review of all randomised clinical trials of adjuvant chemotherapy for gastric cancer compared with surgery alone, published before January 2000, were considered. Pooling of data was performed using the fixed effect model. Death for any cause was the study endpoint. The hazard ratio and its 95% confidence intervals (95% CI), derived according to the method of Parmar, were the statistics chosen for summarising the relative benefit of chemotherapy versus control.

RESULTS

Overall 20 articles (21 comparisons) were considered for analysis. Three studies used single agent chemotherapy, seven combination of 5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU without anthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82, 95% CI: 0.75-0.89, P < 0.001). Association of Anthracyclines to 5-FU did not show a statistically significant improvement when compared with the effect of the other regimens.

CONCLUSIONS

Chemotherapy produces a small survival benefit in patients with curatively resected gastric cancer. However, taking into account the limitations of literature based meta-analyses, adjuvant chemotherapy is still to be considered as an investigational approach.

Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox5, BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells.

The influence of cholesterol on the phase behavior of glycerophospholipids and sphingomyelins was investigated by spin-label electron spin resonance (ESR) spectroscopy. 4-(4,4-Dimethyl-3-oxy-2-tridecyl-2-oxazolidinyl)butanoic acid (5-SASL) and 1-stearoyl-2-[4-(4,4-dimethyl-3-oxy-2-tridecyl-2-oxazolidinyl)butanoy l]-sn- glycero-3-phosphocholine (5-PCSL) spin-labels were employed for this purpose. The outer hyperfine splitting constants, Amax, measured from the spin-label ESR spectra as a function of temperature were taken as empirical indicators of cholesterol-induced changes in the acyl chain motions in the fluid state. The Amax values of 5-PCSL exhibit a triphasic dependence on the concentration of cholesterol for phosphatidylcholines and bovine brain sphingomyelin. We interpret this dependence as reflecting the existence of liquid-disordered, ld, liquid-ordered, lo, and coexistence regions, ld + lo. The phase boundary between the ld and the two-phase region and the boundary between the lo and the two-phase region in the phosphatidylcholine-cholesterol systems coalesce at temperatures 25-33 degrees C above the main-chain melting transition temperature of the cholesterol-free phosphatidylcholine bilayers. In the case of bovine brain sphingomyelin, the ld-lo phase coalescence occurs about 47 degrees C above the melting temperature of the pure sphingomyelin. The selectivity of interaction of cholesterol with glycerophospholipids of varying headgroup charge was studied by comparing the cholesterol-induced changes in the Amax values of derivatives of phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidylserine spin-labeled at the fifth position of the sn-2 chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Our understanding of multisensory integration has advanced because of recent functional neuroimaging studies of three areas in human lateral occipito-temporal cortex: superior temporal sulcus, area LO and area MT (V5). Superior temporal sulcus is activated strongly in response to meaningful auditory and visual stimuli, but responses to tactile stimuli have not been well studied. Area LO shows strong activation in response to both visual and tactile shape information, but not to auditory representations of objects. Area MT, an important region for processing visual motion, also shows weak activation in response to tactile motion, and a signal that drops below resting baseline in response to auditory motion. Within superior temporal sulcus, a patchy organization of regions is activated in response to auditory, visual and multisensory stimuli. This organization appears similar to that observed in polysensory areas in macaque superior temporal sulcus, suggesting that it is an anatomical substrate for multisensory integration. A patchy organization might also be a neural mechanism for integrating disparate representations within individual sensory modalities, such as representations of visual form and visual motion.

We reviewed articles on the epidemiology and clinical characteristics of gastroesophageal reflux disease (GERD) in Japan to clarify these features of GERD in this country. Although the definition of GERD depends on the individual study, the prevalence of GERD has been increasing since the end of the 1990s. The reasons for the increase in the prevalence of GERD may be due to increases in gastric acid secretion, a decrease in the Helicobacter pylori infection rate, more attention being paid to GERD, and advances in the concept of GERD. More than half of GERD patients had non-erosive reflux disease, and the majority (87%) of erosive esophagitis was mild type, such as Los Angeles classification grade A and grade B. There were several identified risk factors, such as older age, obesity, and hiatal hernia. In particular, mild gastric atrophy and absence of H. pylori infection influence the characteristics of GERD in the Japanese population. We also discuss GERD in the elderly; asymptomatic GERD; the natural history of GERD; and associations between GERD and peptic ulcer disease and H. pylori eradication. We examined the prevalence of GERD in patients with specific diseases, and found a higher prevalence of GERD, compared with that in the general population, in patients with diabetes mellitus, those with obstructive sleep apnea syndrome, and those with bronchial asthma. We provide a comprehensive review of GERD in the Japanese population and raise several clinical issues.

Although the absolute number of memory CD8+ T cells established in the spleen following antigen encounter remains stable for many years, the relative capacity of these cells to mediate recall responses is not known. Here we used a dual adoptive transfer approach to demonstrate a progressive increase in the quality of memory T cell pools in terms of their ability to proliferate and accumulate at effector sites in response to secondary pathogen challenge. This temporal increase in efficacy occurred in CD62L lo (effector memory) and CD62L hi (central memory) subpopulations, but was most prominent in the CD62L hi subpopulation. These data indicate that the contribution of effector memory and central memory T cells to the recall response changes substantially over time.

OBJECTIVE

Hypoglycemia is associated with adverse outcomes in mixed populations of patients in intensive care units. It is not known whether the same risks exist for diabetic patients who are less severely ill. In this study, we aimed to determine whether hypoglycemic episodes are associated with higher mortality in diabetic patients hospitalized in the general ward.

METHODS

This retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes hospitalized in the general ward of a teaching hospital between January 2003 and August 2004. The associations between the number and severity of hypoglycemic (<or=50 mg/dl) episodes and inpatient mortality, length of stay (<em>LOS</em>), and mortality within 1 year after discharge were evaluated.

RESULTS

Hypoglycemia was observed in 7.7% of admissions. In multivariable analysis, each additional day with hypoglycemia was associated with an increase of 85.3% in the odds of inpatient death (P = 0.009) and 65.8% (P = 0.0003) in the odds of death within 1 year from discharge. The odds of inpatient death also rose threefold for every 10 mg/dl decrease in the lowest blood glucose during hospitalization (P = 0.0058). LOS increased by 2.5 days for each day with hypoglycemia (P < 0.0001).

CONCLUSIONS

Hypoglycemia is common in diabetic patients hospitalized in the general ward. Patients with hypoglycemia have increased LOS and higher mortality both during and after admission. Measures should be undertaken to decrease the frequency of hypoglycemia in this high-risk patient population.

Objective: To analyse genome variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Methods: Between 1 February and 1 May 2020, we downloaded 10 022 SARS CoV-2 genomes from four databases. The genomes were from infected patients in 68 countries. We identified variants by extracting pairwise alignment to the reference genome NC_045512, using the EMBOSS needle. Nucleotide variants in the coding regions were converted to corresponding encoded amino acid residues. For clade analysis, we used the open source software Bayesian evolutionary analysis by sampling trees, version 2.5.

Findings: We identified 5775 distinct genome variants, including 2969 missense mutations, 1965 synonymous mutations, 484 mutations in the non-coding regions, 142 non-coding deletions, 100 in-frame deletions, 66 non-coding insertions, 36 stop-gained variants, 11 frameshift deletions and two in-frame insertions. The most common variants were the synonymous 3037C > T (6334 samples), P4715L in the open reading frame 1ab (6319 samples) and D614G in the spike protein (6294 samples). We identified six major clades, (that is, basal, D614G, L84S, L3606F, D448del and G392D) and 14 subclades. Regarding the base changes, the C > T mutation was the most common with 1670 distinct variants.

Conclusion: We found that several variants of the SARS-CoV-2 genome exist and that the D614G clade has become the most common variant since December 2019. The evolutionary analysis indicated structured transmission, with the possibility of multiple introductions into the population.

Objectif: Analyser les variantes du génome de coronavirus 2 du syndrome respiratoire aigu sévère (SARS-CoV-2).

Méthodes: Entre le 1^er février et le 1^er mai 2020, nous avons téléchargé 10 022 génomes de SARS CoV-2 issus de quatre bases de données. Ces génomes provenaient de patients infectés originaires de 68 pays. Nous avons identifié les variantes en procédant à un alignement par paires avec la séquence de référence NC_045512, à l'aide de l'outil EMBOSS Needle. Les variantes de nucléotides dans les régions codantes ont été converties en résidus d'acides aminés codés correspondants. Enfin, pour analyser le clade, nous avons employé un logiciel open source appelé Bayesian Evolutionary Analysis by Sampling Trees, version 2.5.

Résultats: Nous avons détecté 5775 variantes de génome distinctes, dont 2969 mutations faux-sens, 1965 mutations synonymes, 484 mutations dans les régions non codantes, 142 délétions non codantes, 100 délétions sans décalage du cadre de lecture, 66 insertions non codantes, 36 variantes de codon stop, 11 délétions entraînant un décalage du cadre de lecture, et 2 insertions sans décalage du cadre de lecture. Les variantes les plus fréquentes étaient les synonymes 3037C > T (6334 échantillons), P4715L dans le cadre ouvert de lecture 1ab (6319 échantillons) et D614G dans la protéine de spicule (6294 échantillons). Nous avons identifié six clades majeurs (à savoir, de base, D614G, L84S, L3606F, D448del et G392D) et 14 sous-clades. Quant aux changements de base, la mutation C > T était la plus répandue avec 1670 variantes distinctes.

Conclusion: Nous avons constaté qu'il existait de nombreuses variantes du génome de SARS-CoV-2, et que le clade D614G était devenu la variante la plus commune depuis décembre 2019. L'analyse évolutive a indiqué une transmission structurée, avec une possibilité d'introductions multiples au sein de la population.

Objetivo: Analizar las variantes del genoma del coronavirus tipo 2 del síndrome respiratorio agudo grave (SARS-CoV-2).

Métodos: Entre el 1 de febrero y el 1 de mayo de 2020, se registraron 10 022 genomas del CoV-2 del SARS en cuatro bases de datos. Los genomas eran de pacientes infectados ubicados en 68 países. Se identificaron variantes al extraer la alineación por pares del genoma de referencia NC_045512, por medio de EMBOSS Needle. Las variantes de los nucleótidos en las regiones codificantes se convirtieron en los correspondientes residuos de aminoácidos codificados. Para analizar los clados, se utilizó el programa informático de código abierto Bayesian evolutionary analysis by sampling trees, versión 2.5.

Resultados: Se identificaron 5775 variaciones diferentes del genoma, incluidas 2969 mutaciones con cambio de sentido, 1965 mutaciones sinónimas, 484 mutaciones en las regiones no codificantes, 142 supresiones no codificantes, 100 supresiones en la fase, 66 inserciones no codificantes, 36 variaciones de parada prematuras (stop-gained), 11 supresiones de desplazamiento de fase y dos inserciones en la fase. Las variaciones más comunes eran las sinónimas 3037C > T (6334 muestras), P4715L en la fase abierta de lectura 1ab (6319 muestras) y D614G en la proteína S (6294 muestras). Se identificaron seis clados principales, (es decir, basal, D614G, L84S, L3606F, D448del y G392D) y 14 subclados. En relación con los cambios de base, la mutación C > T fue la más común con 1670 variaciones diferentes.

Conclusión: Se determinó que existen diversas variaciones del genoma del SARS-CoV-2 y que el clado D614G es la variante más común desde diciembre de 2019. El análisis evolutivo indicó una transmisión estructurada, en la que existe la posibilidad de que se realicen múltiples inserciones en la población.

الغرض تحليل الأشكال المختلفة لجينوم المتلازمة التنفسية الحادة الشديدة المعروفة باسم كورونا فيروس 2 (سارس كوف 2). الطريقة خلال الفترة ما بين 1 فبراير/شباط، و1 مايو/أيار 2020، قمنا بتنزيل 10022 من جينوم سارس كوف 2 من أربع قواعد بيانات. كانت الجينومات من المرضى حاملي العدوى في 68 دولة. قمنا بتحديد أشكال مختلفة عن طريق استخلاص تنسيق على شكل زوجي من الجينوم المرجعي NC_045512، باستخدام إبرة EMBOSS. تم تحويل الأشكال المختلفة من النيوكليتويد في مناطق الترميز إلى بقايا الحمض الأميني المشفر المقابل. وبالنسبة لتحليل كليد، فقد استخدمنا تحليل بايزان المتطور لبرنامج المصدر المفتوح، عن طريق تفرعات العينات، الإصدار 2.5. النتائج حددنا 5775 شكلاً مختلفاً ومتميزاً من الجينوم، بما في ذلك 2969 طفرة مُغلطة، و1965 طفرة متشابهة، و484 طفرة في المناطق غير المشفرة، و142 حالة حذف غير مشفرة، و100 حالة حذف في الإطار، و66 إدخال غير مشفر، و36 شكلاً مكتسبًا موقوفاً، و11 حالة حذف لإزاحة الإطار، وعمليتي إدراج داخل الإطار. كانت أكثر الأشكال المختلفة شيوعاً هي المشابه 3037C > T (6334 عينة)، وP4715L في إطار القراءة المفتوحة 1ab (6319 عينة)، وD614G في بروتين الشوكي (6294 عينة). قمنا بتحديد ستة عوامل كليد أساسية (وهي القاعدي، وD614G، وL84S، وL3606FK، D448del، وG392D)، و14 عاملاً فرعياً من كليد. وبخصوص التغييرات القاعدية، فإن طفرة C > T، كانت الأكثر شيوعاً في 1670 شكلاً مختلفاً ومتميزاً. الاستنتاج لقد اكتشفنا أن هناك العديد من الأشكال المختلفة من جينوم سارس كوف 2، وأن كليد D614G قد أصبح الشكل المختلف الأكثر شيوعاً منذ ديسمبر/كانون أول 2019. أشار التحليل المتطور إلى انتقال منظم، مع إمكانية الظهور المتعدد في السكان.

目的: 旨在分析严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的基因组变异体情况。.

方法: 在 2020 年 2 月 1 日至 5 月 1 日期间，我们从四个数据库下载了 10,022 个严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 基因组。这些基因组来自 68 个国家的感染患者。我们通过使用凸出针提取参考基因组 NC_045512 的成对序列比对来确定变异体。编码区的核苷酸变体被转化为相应的编码氨基酸残基。我们使用基于抽样树的开源软件贝叶斯演化分析（2.5 版）进行支系分析。.

结果: 我们确定了 5775 个不同的基因组变异体，包括 2969 个错义突变、1965 个同义突变、484 个非编码区突变、142 个非编码缺失、100 个框架内缺失、66 个非编码插入、36 个止损变异体、11 个移码缺失和 2 个框架内插入。最常见的变异是同义 3037C > T（6334 个样本）、开放阅读框 1ab 中的 P4715L（6319 个样本）和纤突蛋白中的 D614G（6294 个样本）。我们确定了 6 大主要分支（即，基底、D614G、L84S、L3606F、D448del 和 G392D）和 14 个子分支。在基底变化方面，以 C > T 突变最为常见，共有 1670 个不同的变异体。.

结论: 我们发现严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 基因组存在多种变异体，其中 D614G 支系自 2019 年 12 月以来已成为最常见的变异体。演化分析表明，这是一种结构化传播，有可能多次传入人群中。.

Цель: Проанализировать варианты геномов тяжелого острого респираторного синдрома, вызванного коронавирусом‑2 (SARS-CoV-2).

Методы: В период между 1 февраля и 1 мая 2020 года авторы загрузили данные по 10 022 геномам вируса SARS CoV-2 из четырех баз данных. Геномы принадлежали инфицированным пациентам из 68 стран. Авторы идентифицировали варианты, извлекая и попарно сравнивая последовательности с эталонным геномом NC_045512, используя набор инструментов EMBOSS. Варианты нуклеотидной последовательности в кодирующих участках были преобразованы в соответствующие кодируемые аминокислотные остатки. Для анализа клад использовалось программное обеспечение с открытым кодом для байесовского эволюционного анализа деревьев выборки, версия 2.5.

Результаты: Было идентифицировано 5775 четких вариантов генома, в том числе 2969 миссенс-мутаций, 1965 синонимичных мутаций, 484 мутации в некодирующих участках, 142 некодирующие делеции, 100 делеций внутри рамки считывания, 66 некодирующих вставок, 36 вариантов изменения последовательности ДНК с новым стоп-кодоном, 11 делеций со сдвигом рамки и две вставки внутри рамки считывания. Чаще всего встречались синонимичная замена 3037C > T (6334 образца), P4715L в открытой рамке считывания 1ab (6319 образцов) и D614G в белке «шипа» (6294 образца). Было выявлено шесть основных клад (базовая, D614G, L84S, L3606F, D448del и G392D) и 14 субклад. Что касается замены оснований, наиболее частой была мутация с заменой цитозина на тимин (C>T), которая встречалась в 1670 вариантах.

Вывод: Авторы обнаружили существование нескольких вариантов генома SARS-CoV-2 и выяснили, что с декабря 2019 года наиболее распространенным вариантом является клада D614G. Эволюционный анализ продемонстрировал структурированную передачу генетических данных с возможностью многократной интродукции в популяцию.

Cell surface-located sialic acids of the capsule and the lipooligosaccharide (LOS) are both pivotal virulence factors in Neisseria meningitidis, promoting survival and dissemination of this pathogen which can cause both sepsis and meningitis. With the aid of a unique set of isogenic meningococcal mutants defective in the expression of cell surface-located sialic acids, we have demonstrated that encapsulation hinders the primary event in the development of the disease, but the spontaneous switching of encapsulated wild-type bacteria to a capsule-negative phenotype promotes meningococcal adherence and invasion into mucosal epithelial cells. Genetic analysis of the capsule-negative, invasive bacteria revealed a unique mechanism for modulation of capsule expression based on the reversible inactivation of an essential sialic acid biosynthesis gene, siaA, by insertion/excision of a naturally occurring insertion sequence element, IS1301. Inactivation of siaA regulates both capsule expression and endogenous LOS sialylation. This is the first example of an insertion sequence element-based genetic switch mechanism in the pathogenic bacterium and is an important step in the understanding of bacterial virulence.

Nontypeable Haemophilus influenzae (NTHI) strains are members of the normal human nasopharyngeal flora, as well as frequent opportunistic pathogens of both the upper and lower respiratory tracts. Recently, it has been shown that NTHI can form biofilms both in vitro and in vivo. NTHI strains within in vitro-formed biofilms differentially express both epitopes of lipooligosaccharide (LOS) and the outer membrane proteins P2, P5, and P6, whereas those generated either in a 96-well plate assay in vitro or in a mammalian host have been shown to incorporate a specific glycoform of sialylated LOS within the biofilm matrix. While DNA has been identified as a key component of the biofilm matrix formed in vitro by several bacterial pathogens, here we demonstrate for the first time that in addition to sialylated LOS, the biofilm formed by NTHI in vivo contains both type IV pilin protein and a significant amount of double-stranded DNA. The DNA appeared to be arranged in a dense interlaced meshwork of fine strands as well as in individual thicker "ropes" that span water channels, suggesting that DNA could be imparting structural stability to the biofilm produced by NTHI in vivo. The presence of type IV pilin protein both appearing as small aggregates within the biofilm matrix and tracking along DNA strands supports our observations which showed that type IV pili are expressed by NTHI during experimental otitis media when these bacteria form a biofilm in the middle ear space.

We evaluated the effect of carbon monoxide (CO) exposures during the last trimester of pregnancy on the frequency of low birth weight among neonates born 1989-1993 to women living in the Los Angeles, California, area. Using birth certificate data for that period, we assembled a retrospective cohort of infants whose mothers resided within 2 miles of 1 of 18 CO monitoring stations. Based on the gestational age and birth date of each child, we estimated last-trimester exposure by averaging the corresponding 3 months of daily CO concentrations registered at the monitoring station closest to the mother's residence (determined from the birth certificate). Where data were available (at 6 stations), we also averaged measurements taken daily for nitrogen dioxide and ozone and those taken at 6-day intervals for particulate matter [less than/equal to]10 microm (PM10) to approximate last-trimester exposures to other pollutants. Overall, the study cohort consisted of 125,573 singleton children, excluding infants born before 37 or after 44 weeks of gestation, those weighing below 1,000 or above 5,500 g at birth, those for whom fewer than 10 days of CO measurements were available during the last trimester, and those whose mothers suffered from hypertension, diabetes, or uterine bleeding during pregnancy. Within the cohort, 2,813 (2.2%) were low in birth weight (between 1,000 and 2,499 g). Exposure to higher levels of ambient CO (>5.5 ppm 3-month average) during the last trimester was associated with a significantly increased risk for low birth weight [odds ratio (OR) = 1.22; 95% confidence interval (CI), 1.03-1.44] after adjustment for potential confounders, including commuting habits in the monitoring area, sex of the child, level of prenatal care, and age, ethnicity, and education of the mother.

Braille reading depends on remarkable adaptations that connect the somatosensory system to language. We hypothesized that the pattern of cortical activations in blind individuals reading Braille would reflect these adaptations. Activations in visual (occipital-temporal), frontal-language, and somatosensory cortex in blind individuals reading Braille were examined for evidence of differences relative to previously reported studies of sighted subjects reading print or receiving tactile stimulation. Nine congenitally blind and seven late-onset blind subjects were studied with fMRI as they covertly performed verb generation in response to reading Braille embossed nouns. The control task was reading the nonlexical Braille string "######". This study emphasized image analysis in individual subjects rather than pooled data. Group differences were examined by comparing magnitudes and spatial extent of activated regions first determined to be significant using the general linear model. The major adaptive change was robust activation of visual cortex despite the complete absence of vision in all subjects. This included foci in peri-calcarine, lingual, cuneus and fusiform cortex, and in the lateral and superior occipital gyri encompassing primary (V1), secondary (V2), and higher tier (VP, V4v, LO and possibly V3A) visual areas previously identified in sighted subjects. Subjects who never had vision differed from late blind subjects in showing even greater activity in occipital-temporal cortex, provisionally corresponding to V5/MT and V8. In addition, the early blind had stronger activation of occipital cortex located contralateral to the hand used for reading Braille. Responses in frontal and parietal cortex were nearly identical in both subject groups. There was no evidence of modifications in frontal cortex language areas (inferior frontal gyrus and dorsolateral prefrontal cortex). Surprisingly, there was also no evidence of an adaptive expansion of the somatosensory or primary motor cortex dedicated to the Braille reading finger(s). Lack of evidence for an expected enlargement of the somatosensory representation may have resulted from balanced tactile stimulation and gross motor demands during Braille reading of nouns and the control fields. Extensive engagement of visual cortex without vision is discussed in reference to the special demands of Braille reading. It is argued that these responses may represent critical language processing mechanisms normally present in visual cortex.