Mechanical and Electrical Characteristics of Lightweight Aggregate Concrete Reinforced with Steel Fibers.
There is increased interest in applying electromagnetic (EM) shielding to prevent EM interference, which destroys electronic circuits. The EM shielding's performance is closely related to the electrical conductivity and can be improved by incorporating conductive materials. The weight of a structure can be reduced by incorporating lightweight aggregates and replacing the steel rebars with CFRP rebars. In this study, the effects of lightweight coarse aggregate and CFRP rebars on the mechanical and electrical characteristics of concrete were investigated, considering the steel fibers' incorporation. The lightweight coarse aggregates decreased the density and strength of concrete and increased the electrical conductivity of the concrete, owing to its metallic contents. The steel fibers further increased the electrical conductivity of the lightweight aggregate concrete. These components improved the EM shielding performance, and the steel fibers showed the best performance by increasing shielding effectiveness by at least 23 dB. The CFRP rebars behaved similarly to steel rebars because of their carbon fiber content. When no steel fiber was mixed, the shielding effectiveness increased by approximately 2.8 times with reduced spacing of CFRP rebars. This study demonstrates that lightweight aggregate concrete reinforced with steel fibers exhibits superior mechanical and electrical characteristics for concrete and construction industries.


Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states.
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.


Association of human disturbance and gastrointestinal parasite infection of yellow baboons in western Tanzania.
Human disturbance is an ongoing threat to many wildlife species, manifesting as habitat destruction, resource overuse, or increased disease exposure, among others. With increasing human: non-human primate (NHP) encounters, NHPs are increasingly susceptible to human-introduced diseases, including those with parasitic origins. As such, epidemiology of parasitic disease is becoming an important consideration for NHP conservation strategies. To investigate the relationship between parasite infections and human disturbance we studied yellow baboons (Papio cynocephalus) living outside of national park boundaries in western Tanzania, collecting 135 fresh faecal samples from nine troops occupying areas with varying levels of human disturbance. We fixed all samples in 10% formalin and later evaluated parasite prevalence and abundance (of isotrichid ciliates and Strongylida). We identified seven protozoan and four helminth taxa. Taxa showed varied relationships with human disturbance, baboon troop size and host age. In four taxa, we found a positive association between prevalence and troop size. We also report a trend towards higher parasite prevalence of two taxa in less disturbed areas. To the contrary, high levels of human disturbance predicted increased abundance of isotrichid ciliates, although no relationship was found between disturbance and Strongylida abundance. Our results provide mixed evidence that human disturbance is associated with NHP parasite infections, highlighting the need to consider monitoring parasite infections when developing NHP conservation strategies.


ACR Appropriateness Criteria® Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer.
Patients with locally advanced invasive breast cancers are often treated with neoadjuvant chemotherapy prior to definitive surgical intervention. The primary aims of this approach are to: 1) reduce tumor burden thereby permitting breast conservation rather than mastectomy; 2) promptly treat possible metastatic disease, whether or not it is detectable on preoperative staging; and 3) potentially tailor future chemotherapeutic decisions by monitoring in-vivo tumor response. Accurate radiological assessment permits optimal management and planning in this population. However, assessment of tumor size and response to treatment can vary depending on the modality used, the measurement technique (such as single longest diameter, 3-D measurements, or calculated tumor volume), and varied response of different tumor subtypes to neoadjuvant chemotherapy (such as concentric shrinkage or tumor fragmentation). As discussed in further detail, digital mammography, digital breast tomosynthesis, US and MRI represent the key modalities with potential to help guide patient management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Cognitive strategies shift information from single neurons to populations in prefrontal cortex.
Neurons in primate lateral prefrontal cortex (LPFC) play a critical role in working memory (WM) and cognitive strategies. Consistent with adaptive coding models, responses of these neurons are not fixed but flexibly adjust on the basis of cognitive demands. However, little is known about how these adjustments affect population codes. Here, we investigated ensemble coding in LPFC while monkeys implemented different strategies in a WM task. Although single neurons were less tuned when monkeys used more stereotyped strategies, task information could still be accurately decoded from neural populations. This was due to changes in population codes that distributed information among a greater number of neurons, each contributing less to the overall population. Moreover, this shift occurred for task-relevant, but not irrelevant, information. These results demonstrate that cognitive strategies that impose structure on information held in mind rearrange population codes in LPFC, such that information becomes more distributed among neurons in an ensemble.


Clinical application of nonacoustic middle ear muscle stimulation.
Several clinical situations exist when only nonacoustic stimuli will provide data necessary for the correct neuro-otologic diagnosis. The tactile stapedius and the orbital air-jet reflexes have been used to aid in detecting the middle ear status in severe hearing losses, retrocochlear hearing losses, ossicular fixation, and facial paralysis. These reflexes also are useful in localization in some cranial nerve disorders. The equipment required to elicit these reflexes is inexpensive, and the test can be performed rapidly. Some pitfalls in interpretation are caused by the lack of precise correlative data. When properly used, performed, and interpreted, nonacoustic reflex response data supply information to the clinician that is otherwise unobtainable.


Racial differences in birth outcomes and costs in relation to prenatal WIC participation.
Wide disparities in birth outcomes persist between Black and non-Black women giving birth in the United States, despite medical and social interventions. This research, which examines birth outcomes and cost for infant hospitalization at delivery for Black and non-Black Medicaid clients in relation to the level of prenatal participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), lead to the conclusion that prenatal WIC participation was associated with lower costs to Medicaid and better birth outcomes, particularly for Blacks.


Coinfection with viruses carrying the v-Ha-ras and v-myc oncogenes leads to growth factor independence by an indirect mechanism.
The concomitant expression of certain oncogenes can transform normal diploid rodent cells into transplantable tumorigenic cells. The mechanism by which these oncogenes collaborate is unclear. Recent findings (M. Oshimura, T. M. Gilmer, and J. C. Barrett, Nature [London] 316:636-639, 1985) raise the possibility that karyotypic changes, including monosomy for chromosome 15, are required to induce tumorigenicity in Syrian hamster embryo cells transfected in vitro with v-Ha-ras and v-myc DNAs. We studied the effect of the oncogenes v-Ha-ras and v-myc, introduced by viral infection, on murine hematopoietic cells. The induction of growth factor independence by the two oncogenes was used as an in vitro correlate of tumorigenicity. After a period of reduced growth rate reminiscent of the growth rate of cells in crisis, the doubly infected cells became growth factor independent. These cells showed a great variability in their karyotypes.


Improving combined diabetes outcomes by adding a simple patient intervention to physician feedback: a cluster randomized trial.
Research on synergistic effects of patient targeted interventions combined with physician-targeted interventions has been limited. To compare a combined physician-patient intervention to physician feedback alone on a composite outcome of glycemic, lipid and blood pressure control. In this cluster study 417 patients with adult-type 2 diabetes from four primary care clinics were randomized to receive either a physician-only intervention or a combined physician-plus-patient intervention. Physicians in all clinics received diabetes-related quality performance feedback during staff meetings. Patients at combined-intervention clinics also received a letter encouraging them to remind their doctors to address essential aspects of diabetes care at the next visit. At 1 year follow-up, outcome measurements included hemoglobin A1c, low density lipoprotein-cholesterol and systolic blood pressure: namely, the proportion of patients with HbA1c 9%, LDL <130 mg/dl and SBP <140 mmHg both as separate outcomes and combined. After adjusting for patient characteristics and baseline measures, follow-up levels of HbA1c (7.5% vs. 7.8%, P = 0.09), LDL (104.7 vs. 110.7 mg/dl, P < 0.05) and SBP (135.6 vs. 139.9, P = 0.10) were marginally better for combined-intervention patients compared to physician-only intervention patients. Significantly more patients in the combined-intervention (38.8%) than physician-only intervention (24.2%) met all three targets (HbA1c (9%, LDL (130 mg/dl and SBP <140 mmHg) as a single combined outcome (adjusted odds ratio 2.4, P < .01). Compared to physician-feedback alone, a dual intervention combining a patient letter with physician feedback produced modest improvements in glycemic, lipid and blood pressure control individually, but substantial improvement in a combined measure of these three outcomes together. Using composite outcomes may detect meaningful improvements in the management of complex chronic disease.


Risk factors for COVID-19 diagnosis, hospitalization, and subsequent all-cause mortality in Sweden: a nationwide study.
We conducted a nationwide, registry-based study to investigate the importance of 34 potential risk factors for coronavirus disease 2019 (COVID-19) diagnosis, hospitalization (with or without intensive care unit [ICU] admission), and subsequent all-cause mortality. The study population comprised all COVID-19 cases confirmed in Sweden by mid-September 2020 (68,575 non-hospitalized, 2494 ICU hospitalized, and 13,589 non-ICU hospitalized) and 434,081 randomly sampled general-population controls. Older age was the strongest risk factor for hospitalization, although the odds of ICU hospitalization decreased after 60-69 years and, after controlling for other risk factors, the odds of non-ICU hospitalization showed no trend after 40-49 years. Residence in a long-term care facility was associated with non-ICU hospitalization. Male sex and the presence of at least one investigated comorbidity or prescription medication were associated with both ICU and non-ICU hospitalization. Three comorbidities associated with both ICU and non-ICU hospitalization were asthma, hypertension, and Down syndrome. History of cancer was not associated with COVID-19 hospitalization, but cancer in the past year was associated with non-ICU hospitalization, after controlling for other risk factors. Cardiovascular disease was weakly associated with non-ICU hospitalization for COVID-19, but not with ICU hospitalization, after adjustment for other risk factors. Excess mortality was observed in both hospitalized and non-hospitalized COVID-19 cases. These results confirm that severe COVID-19 is related to age, sex, and comorbidity in general. The study provides new evidence that hypertension, asthma, Down syndrome, and residence in a long-term care facility are associated with severe COVID-19.


Molecular characterization of seven genes encoding ethylene-responsive transcriptional factors during plum fruit development and ripening.
Seven ERF cDNAs were cloned from two Japanese plum (Prunus salicina L.) cultivars, 'Early Golden' (EG) and 'Shiro' (SH). Based on the sequence characterization, these Ps-ERFs could be classified into three of the four known ERF families. Their predicted amino acid sequences exhibited similarities to ERFs from other plant species. Functional nuclear localization signal analyses of two Ps-ERF proteins (Ps-ERF1a and -1b) were carried out using confocal microscopy. Expression analyses of Ps-ERF mRNAs were studied in the two plum cultivars in order to determine the role of this gene family in fruit development and ripening. The seven Ps-ERFs displayed differential expression pattern and levels throughout the various stages of flower and fruit development. The diversity in Ps-ERFs accumulation was largely due to the differences in their responses to the levels of ethylene production. However, other plant hormones such as cytokinin and auxin, which accumulate strongly throughout the various developmental stages, also influence the Ps-ERFs expression. The effect of the plant hormones, gibberellin, cytokinin, auxin, and ethylene in regulating the different Ps-ERF transcripts was investigated. A model was proposed in which the role played by the plant hormone auxin is as important as that of ethylene in initiating and determining the date and rate of ripening in Japanese plums.


HIV and Hepatitis C Among People Who Inject Drugs in Memphis, Tennessee: an Intersectional Risk Environment Analysis of the Social Determinants of Health.
The Southern US is confronting bourgeoning HIV and hepatitis C virus (HCV) epidemics among people who inject drugs (PWID), yet little is known about shared and unique risk factors across the region. We applied an intersectional risk environment framework to understand infectious disease outcomes for sub-groups of PWID that experience multiple axes of social marginalization related to racial and ethnic identity and social and economic vulnerability. HIV and HCV prevalence was estimated from the first iteration of the CDC's National HIV Behavioral Surveillance respondent driven sample of PWID in Shelby County, Tennessee in 2018. We ran adjusted multinomial models to test main and interaction effects of race/ethnicity and structural factors on the prevalence of a three-level outcome: HIV-only, HCV-only, and no infection. A total of 564 PWID participated, 558 (99%) completed HIV testing, and 540 (96%) HCV testing. Thirty (5%) were HIV-positive, 224 (40%) HCV-positive, and less than 1% were co-infected. Descriptive differences by race/ethnicity and levels of structural vulnerability for HIV and HCV subpopulations were present; however, there was no evidence for statistical interaction. In the final main effects model, HIV status was positively associated with non-Hispanic Black identity (aRR 4.95, 95% CI 1.19, 20.6), whereas HCV status was associated with non-white identity (aRR 0.11 95% CI 0.07, 0.18). Factors associated with HCV infection were higher scores of structural vulnerability (aRR 2.19 95% CI 1.10, 4.35), and criminal legal involvement (aOR 1.99 95% CI 1.18, 3.37). This is the first study to implement local population-based survey data to evaluate distinctive intersections of ethnic/racial and social factors associated with HIV and HCV status among PWID in the Memphis region. Findings come at an opportune time as harm reduction programs are in development in the South and shed light to the need for socially equitable race conscious resource investment.


Human anti-idiotypic T cells induced by TCR peptides corresponding to a common CDR3 sequence motif in myelin basic protein-reactive T cells.
T cells recognizing myelin basic protein (MBP) are potentially involved in the pathogenesis of multiple sclerosis (MS). In vivo clonal expansion of MBP-reactive T cells in MS may relate in part to dysfunction of peripheral regulatory mechanisms, including the anti-idiotypic immune network. In this study, we examined anti-idiotypic immune responses and the functional properties of anti-idiotypic T cells in patients with MS and healthy controls using TCR peptides corresponding to a CDR3 sequence motif preferentially expressed among T cells recognizing the 83-99 immunodominant peptide of MBP in some patients with MS. The study demonstrated that anti-idiotypic T cells could be induced in vitro by 8mer and 15mer peptides containing the CDR3 motif in MS patients and healthy controls respectively. The estimated precursor frequency of the anti-idiotypic T cells was slightly reduced in MS patients compared to control subjects. The obtained anti-idiotypic T cells recognizing the 15mer TCR peptide were found to express the CD4 phenotype, produce predominantly IL-10 and inhibit the proliferation of autologous T cells recognizing the immunodominant peptide of MBP. Anti-idiotypic T cells induced by the 8mer TCR peptide were predominantly CD8+ cytotoxic T cells and exhibited cytotoxic activity against autologous MBP-specific T cells expressing the CDR3 sequence. When added in primary culture, both TCR peptides had a significant inhibitory effect on the T cell responses to the immunodominant peptide of MBP. The findings suggest that anti-idiotypic immune responses can be activated by selected TCR peptides and may play an important role in the in vivo regulation of MBP-reactive T cells.


The epigenome and the mitochondrion: bioenergetics and the environment [corrected].
In the July 15, 2010, issue of Genes & Development, Yoon and colleagues (pp. 1507-1518) report that, in a siRNA knockdown survey of 6363 genes in mouse C2C12 cells, they discovered 150 genes that regulated mitochondrial biogenesis and bioenergetics. Many of these genes have been studied previously for their importance in regulating transcription, protein and nucleic acid modification, and signal transduction. Some notable examples include Brac1, Brac2, Pax4, Sin3A, Fyn, Fes, Map2k7, Map3k2, calmodulin 3, Camk1, Ube3a, and Wnt. Yoon and colleagues go on to validate their observations by extensively documenting the role of Wnt signaling in the regulation of mitochondrial function.


Phonological sensitivity and memory in children with a foreign language learning difficulty.
The phonological processing and memory skills of 12- and 13-year-old Italian children with difficulty in learning English as a foreign language (foreign language learning difficulty, FLLD) were examined and compared with those of a control group matched for age and nonverbal intelligence. Three experiments were conducted. A dissociation between verbal and visuo-spatial working memory was observed when compared to the control group; children with FLLD showed a poorer performance in a phonological working memory task but performed to a comparable level in a visuo-spatial working memory task (Experiment 1). In Experiment 2 the word length and the response modality of an auditory word span task were manipulated in order to examine the efficiency of the phonological loop and the relevance of the spoken output. The FLLD group did not show sensitivity to the word length effect and showed no advantage in the picture pointing recall condition. In Experiment 3 children with FLLD were shown to be sensitive to phonological similarity but again they showed neither a word length effect nor a slower articulation speed. Furthermore, in all three experiments children with FLLD were shown to be less efficient in phonological sensitivity tasks and this deficit appeared to be independent of the phonological memory problem. All three experiments consistently showed that children with FLLD have an impairment in phonological memory and phonological processing, which appear to be independent from one other but both contribute to the children's difficulty in learning a second language.


Face recognition using recursive Fisher linear discriminant.
Fisher linear discriminant (FLD) has recently emerged as a more efficient approach for extracting features for many pattern classification problems as compared to traditional principal component analysis. However, the constraint on the total number of features available from FLD has seriously limited its application to a large class of problems. In order to overcome this disadvantage, a recursive procedure of calculating the discriminant features is suggested in this paper. The new algorithm incorporates the same fundamental idea behind FLD of seeking the projection that best separates the data corresponding to different classes, while in contrast to FLD the number of features that may be derived is independent of the number of the classes to be recognized. Extensive experiments of comparing the new algorithm with the traditional approaches have been carried out on face recognition problem with the Yale database, in which the resulting improvement of the performances by the new feature extraction scheme is significant.


Single-walled carbon nanotube coated antibacterial paper: preparation and mechanistic study.
Development of carbon nanotubes toward commercial antibacterial applications warrants the understanding of their interaction mechanism with bacterial cells. The antibacterial activity and mechanism of acid-functionalized single-walled carbon nanotube (AFSWCNT) coated paper was assessed for gram-positive Staphylococcus aureus and gram-negative Escherichia coli models of bacteria. Better activity towards gram-positive bacteria was observed, whereas the presence of an outer membrane makes gram-negative bacteria more resistant to cell membrane damage caused by AFSWCNTs. Based on measured cytoplasmic efflux materials of bacteria, X-ray photoelectron spectroscopy, and scanning transmission electron microscopy combined with electron energy-loss spectroscopy imaging studies, we found that the better antibacterial activity of AFSWCNTs toward gram-positive bacteria is attributed to not only direct physical contact and piercing action, but also molecular-scale interaction with surface functional groups of bacteria. The novel antibacterial mechanism of AFSWCNTs might bring a promising strategy to design new antibacterial materials against drug-resistant bacteria species.


[Hygienic assessment of nutrition in the Primorskiĭ region].
A growing morbidity among the population of the Maritime territory is preconditioned by a worsening social-and-economic situation, and by a sharply falling purchasing capacity of people, which had an absolutely negative effect on the structure of foodstuffs consumption. The qualitatively and quantitatively insufficient nutrition predetermines a deficit of macro- and micronutrient composition of daily ration and its value. Such defects of nutrition have a pronounced negative influence on the population's health and predetermine a high level of diseases of the digestive apparatus.


Efficacy of EUS-guided hepaticogastrostomy in prolonging survival of patients with perihilar cholangiocarcinoma.
The background of this study was to evaluate the outcomes of perihilar cholangiocarcinoma (pCCA) patients treated with EUS-guided hepaticogastrostomy (EUS-HGS). All patients with pCCA who underwent EUS-HGS from 2010 to 2020 were analyzed. The primary outcome was clinical success; the secondary outcomes were technical success, adverse events (AEs), stent patency, and oncological outcomes. Cox proportional-hazards regression and Kaplan-Meier curves were analyzed to identify variables related to survival. Thirty-four patients (50% females, 76 years old) were included; 24 (70.6%) presented with distant metastasis. Indications for EUS-HGS were ERCP failure (64.7%), duodenal stricture (23.5%), postsurgical anatomy (5.9%), and dilation limited to the left intrahepatic duct (5.9%). The technical success rate was 97.1%. The clinical success rate was 64.7%. Nine (26.5%) presented AEs, 2 fatal (bleeding and leakage). The overall survival was 91 (31-263) days. On multivariate analysis, EUS-HGS clinical success (Exp[b]: 0.23 [0.09-0.60]; P = 0.003) and chemotherapy (Exp[b]: 0.06 [0.02-0.23]; P < 0.001) were significantly associated with survival. The survival was longer in patients who achieved EUS-HGS clinical success (178[61-393] vs. 15[73-24] days; hazard ratio: 6.3; P < 0.001) and in those starting chemotherapy (324[178-439] vs. 31 [9-48]; hazard ratio: 1.2; P < 0.001). EUS-HGS is effective in pCCA patients despite a not negligible AE rate. Clinical success, potentially leading to jaundice resolution and chemotherapy start, significantly improves survival.


Spillover of Ratings of Patient- and Family-Centered Care.
As primary care models increasingly include nonphysician team members, more attention should be paid to patient- and family-centered care (PFCC) among medical assistants (MAs). The aims of this article are to describe parent perceptions of PFCC by MAs and assess associations between MA PFCC and other perceptions of their care experience. To assess PFCC, we administered the CARE (Consultation and Relational Empathy) measure to the parent/guardian of 360 children following a primary care visit. Perceptions of PFCC by MAs were significantly associated with 6 of 7 other measures of patient experience, including PFCC by the physician, treatment by the receptionist, and satisfaction with wait time. Each team member can potentially shape perceptions of care in ways that could "spill over" into other parts of the visit.


Major psychosis and chromosome 22: genetics meets epigenetics.
Elucidation of genetic factors in schizophrenia and bipolar disorder remains a challenging task to psychiatric researchers. As a rule, data from genetic linkage and association studies are quite controversial. In this article, we further explore the possibility that in addition to DNA sequences variation, a putative epigenetic dysregulation of brain genes plays an important role in the etiopathogenesis of major psychosis. We provide an epigenetic interpretation of unclear genetic findings specifically pertaining to chromosome 22 in schizophrenia and bipolar disorder. It is suggested that epigenetic strategies, when applied in conjunction with traditional genetic ones, may significantly expedite the uncovering of the molecular causes of major psychosis.


Dynamic stereotactic radiosurgery: the Charleston program: a report on the first 150 patients.
We have been pleased with our initial experience in an evolving program. As newer surgical and radiotherapy techniques have become available, the role of radiosurgery has been and will continue to be modified. As more commercially available systems have been marketed, the availability will become more widespread. A battery of residents in neurosurgery and radiation oncology trained in these technologies will provide leadership and future directions of this therapy.


Outpatient case management in low-income epilepsy patients.
Case management (CM) has been shown to improve the medical care of patients in several paradigms of general medicine. This study was undertaken to assess the impact of CM on low-income patients with epilepsy. From 2002 to 2003, 737 epilepsy patients had CM provided by a non-profit, state-supported, epilepsy service subserving a four county region in southeastern Florida. Standardized survey forms distributed by the Florida Department of Health were completed by 159 consecutive patients at program admission. Follow-up information regarding seizure frequency, antiepileptic drugs, and quality of life self-rating was performed after 1 year of CM. The patients evaluated were composed of 58.5% men, with a mean age of 41.0 years. After CM, an increase in self-reported seizure control was seen in 40.2% of patients (p<0.0001, Fisher's exact test), in addition to a shift in the principal utilization of the older to the newer antiepileptic drugs. Furthermore, the total number of emergency department (ED) visits was reduced by 90% with a mean reduction of ED visits per patient from 1.83 per patient per year before CM to 0.14 per patient per year after CM (p<0.0001, Wilcoxon matched-pairs test). Following CM, fewer patients reported difficulty with friends, employers, problems socializing, and feelings of anger (p<0.05, Fisher's exact test). CM of low-income patients with epilepsy resulted in self-reported improvement in seizure control, QoL, and significantly reduced ED visitation. CM in epilepsy is feasible and represents a cost-effective improvement in outpatient epilepsy management.


Dedicated peri-operative pathway improved day case discharge rate for anterior cruciate ligament reconstructions.
The authors proposed that a well-developed peri-operative pathway for anterior cruciate ligament (ACL) reconstructions improve day case discharge rate with high patient satisfaction. A prospective observational study was undertaken at a district general hospital in UK between August 2017 and April 2018. A dedicated multidisciplinary peri-operative pathway was developed and introduced in January 2018. All primary ACL reconstructions using hamstring grafts in adult patients were included. Primary outcome measure was day case discharge and secondary outcome measures were visual analogue score for pain (VASP), nausea and vomiting scale (NVS), patient satisfaction and 30-day readmission. Patients who underwent surgery before and after introduction of the pathway were in group 1 and group 2, respectively. There were 19 and 22 patients each in group 1 and 2. Age and gender were similar in both groups. Day case discharge rate was significantly better in group 2 (68.4% vs 95.5%, p = 0.02). There were no significant differences in VASP or NVS on day 0, 1 or 3. Patient satisfaction rates were better in group 2 (85.7% vs 100%, p = 0.13). There were no readmissions in both groups. The VASP on day 1 and day 3 post-operatively was significantly better in those who were discharged on the same day (66.8 vs 41.3, p = 0.02; 60.5 vs 34.9, p = 0.03). A well-developed dedicated peri-operative pathway improved day case discharge rate for ACL reconstructions. The pathway was safe and had a higher patient satisfaction rate.


Optimization of megavoltage CT scan registration settings for thoracic cases on helical tomotherapy.
This study aims to investigate the settings that provide optimum registration accuracy when registering megavoltage CT (MVCT) studies acquired on tomotherapy with planning kilovoltage CT (kVCT) studies of patients with lung cancer. For each experiment, the systematic difference between the actual and planned positions of the thorax phantom was determined by setting the phantom up at the planning isocenter, generating and registering an MVCT study. The phantom was translated by 5 or 10 mm, MVCT scanned, and registration was performed again. A root-mean-square equation that calculated the residual error of the registration based on the known shift and systematic difference was used to assess the accuracy of the registration process. The phantom study results for 18 combinations of different MVCT/kVCT registration options are presented and compared to clinical registration data from 17 lung cancer patients. MVCT studies acquired with coarse (6 mm), normal (4 mm) and fine (2 mm) slice spacings could all be registered with similar residual errors. No specific combination of resolution and fusion selection technique resulted in a lower residual error. A scan length of 6 cm with any slice spacing registered with the full image fusion selection technique and fine resolution will result in a low residual error most of the time. On average, large corrections made manually by clinicians to the automatic registration values are infrequent. Small manual corrections within the residual error averages of the registration process occur, but their impact on the average patient position is small. Registrations using the full image fusion selection technique and fine resolution of 6 cm MVCT scans with coarse slices have a low residual error, and this strategy can be clinically used for lung cancer patients treated on tomotherapy. Automatic registration values are accurate on average, and a quick verification on a sagittal MVCT slice should be enough to detect registration outliers.


Soda consumption during ad libitum food intake predicts weight change.
Soda consumption may contribute to weight gain over time. Objective data were used to determine whether soda consumption predicts weight gain or changes in glucose regulation over time. Subjects without diabetes (128 men, 75 women; mean age 34.3±8.9 years; mean body mass index 32.5±7.4; mean percentage body fat 31.6%±8.6%) self-selected their food from an ad libitum vending machine system for 3 days. Mean daily energy intake was calculated from food weight. Energy consumed from soda was recorded as were food choices that were low in fat (<20% of calories from fat) or high in simple sugars (>30%). Food choices were expressed as percentage of daily energy intake. A subset of 85 subjects had measurement of follow-up weights and oral glucose tolerance (57 men, 28 women; mean follow-up time=2.5±2.1 years, range 6 months to 9.9 years). Energy consumed from soda was negatively related to age (r=-0.27, P=0.0001) and choosing low-fat foods (r=-0.35, P<0.0001), but positively associated with choosing solid foods high in simple sugars (r=0.45, P<0.0001) and overall average daily energy intake (r=0.46, P<0.0001). Energy intake from food alone did not differ between individuals who did and did not consume beverage calories (P=0.11). Total daily energy intake had no relationship with change in weight (P=0.29) or change in glucose regulation (P=0.38) over time. However, energy consumed from soda correlated with change in weight (r=0.21, P=0.04). This relationship was unchanged after adjusting for follow-up time and initial weight. Soda consumption is a marker for excess energy consumption and is associated with weight gain.


Inflammatory Demyelinating Diseases of Childhood: Case Report and Literature Review.
Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are demyelinating inflammatory diseases, considered to have a striking pathophysiological resemblance. However, due to the differences in both clinical course and clinical approaches, it is important to differentiate between the two conditions, to plan further investigations and therapy protocols. These diseases have similar but also distinct clinical, radiological and cerebrospinal fluid (CSF) findings. ADEM is typically a monophasic disease of children. MS occurs generally in adult age, but uncommonly may develop in childhood with variable features. Our case is a 14 year-old-girl, presented with a three-month history of left hemiparesis, followed by right hemiparesis, cerebellar signs, myelitis and cortical visual disturbances. Based on the clinical follow-up, MR and CSF findings, our patient was diagnosed with relapsing tumefactive multiple sclerosis. Steroid treatment was not significantly effective, however the patient has benefited from plasmapheresis clinically and radiologically. Our patient is still being followed under the disease modifying therapy without any relapse.


Plasmacytoma of the gastrointestinal tract in Korea: higher incidence than in Japan and Epstein-Barr virus association.
As a result of a systematic review of non-Hodgkin's lymphoma of the gastrointestinal tract (GI) at the Yonsei University, Seoul, Korea and the Osaka University, Osaka, Japan, we found an extramedullary plasmacytoma in 5 of a total of 78 cases (6.4%) in Korea and 1 of 136 cases (0.7%) in Osaka, which represents an approximately 9-fold difference in frequency. The presence of the Epstein-Barr virus (EBV) genome was examined in paraffin-embedded specimens from the 5 cases with GI plasmacytoma from Korea together with 17 patients collected by a nationwide study in Japan. There were no clinical findings suggestive of the presence of immunodeficiency in these Korean and Japanese patients. There were no prominent differences in the age distribution or sex ratio between the patients of the two countries. Histologically, the proliferation of mature plasma cells was almost monomorphous with occasional bi- or multinucleated forms. The immunohistochemistry revealed a restricted cytoplasmic expression of immunoglobulin light chain, kappa type in 8 cases and lambda type in 14. A polymerase chain reaction of preserved DNA from 4 Korean and 16 Japanese patients found that only 2, both Korean, were positive for EBV of subtype A. The difference in the frequency of EBV positivity between Korean and Japanese cases was significant (p < 0.05). In situ hybridization revealed positive signals in the nucleus of the tumor cells. IHC revealed that the tumor cells in these two cases were positive for latent membrane protein-1 and EB nuclear antigen-2, showing latent infection of EBV. These findings suggest a close association of EBV and Korean GI plasmacytoma, and might partly explain the remarkable number of cases in this country.


OSeMOSYS Global, an open-source, open data global electricity system model generator.
This paper describes OSeMOSYS Global, an open-source, open-data model generator for creating global electricity system models for an active global modelling community. This version of the model generator is freely available and can be used to create interconnected electricity system models for both the entire globe and for any geographically diverse subset of the globe. Compared to other existing global models, OSeMOSYS Global allows for full user flexibility in determining the time slice structure and geographic scope of the model and datasets, and is built using the widely used fully open-source OSeMOSYS energy system model. This paper describes the data sources, structure and use of OSeMOSYS Global, and provides illustrative workflow results.


[Anorexia nervosa and bulimia nervosa. IIi. Somatic complications of purging].
Patients with anorexia nervosa or bulimia nervosa may try to compensate weight gain due to binge eating by purging: vomiting or use of diuretics, laxatives or diet pills. Purging may reduce the body weight through volume depletion, but has hardly any effect on the food uptake. Frequent vomiting is revealed by enlargement of the submandibular and parotid glands and rise of the serum amylase. Use of laxatives leads to electrolyte imbalances, lesions of intestinal mucosa and chronic obstipation. Physical effects of diuretics are dehydration and electrolyte imbalance; oedema may be a sign of their discontinuation. Frequent or major effects of purging are: disorders of cardiac conduction (caused by hypokalaemia), insults and cerebral dysfunction (both due to hyponatraemia). A normal serum potassium concentration does not exclude intracellular hypokalaemia; accordingly, electrocardiography is indicated.


[Mechanical ventilation on paediatric intensive care units in Czech Republic].
The aims of this study were to evaluate the incidence of mechanically ventilated children in participating units, to find out the demographic data of the patients, to evaluate ventilator settings and to assess the mortality of ventilated children. Prospective observational multicenter study between 1. 2. 2002 and 30. 4. 2002. Seven paediatric intensive care units in tertiary hospitals in the Czech Republic. All children between 1 month and 18 years admitted to the participating paediatric intensive care units who required intubation and mechanical ventilation were enrolled. Following parameters were recorded in all patients: demographic data (age, weight, gender), the origin of the admitting diagnosis, severity of illness (Pediatric Risk of Mortality Score - PRISM, Multiorgan System Failure - MOSF, Lung Injury Score - LIS), the origin of respiratory failure, presence of chronic disease and immunosuppression, length of ventilation, length of stay, ventilator setting, the use of unconventional ventilation, outcome (mortality), blood gas analyses and indices (alveoloarterial oxygen difference - AaDO (2), oxygenation index - OI, hypoxemia score - PaO (2)/FiO (2) and ventilation index - VI), deadspace to tidal volume ratio-Vd/Vt and dynamic respiratory system compliance (Cdyn). One hundred and forty four children (42 % girls) were enrolled in total which represent 23 % of all admitted children. The mean age of the patients was 70 months and mean weight was 23 kg. PRISM score and the length of stay were twofold against mean values (11.7 vs. 5.7 and 10.4 vs. 4.8 days respectively). The mean length of ventilation was 117 hours, 66 % of the patients had an extrapulmonary origin of respiratory failure, 19 % of the patients were chronically ill, and 0,7 % had the evidence of immunosuppression. Pressure regulated volume controlled and Biphasic positive airway pressure were the most frequently used ventilator settings. Unconventional ventilation in all was used in 13 % of the patients. Mortality was 3.5 %. Children on mechanical ventilation create 23 % of all patients admitted to paediatric intensive care units. The severity of illness and length of stay were twofold against mean values. Mortality rate was 3.5 % and hypoxia was not a cause of death in any patient.


Population-specific single-nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans.
African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized. We performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP). In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10). We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.


Sepsis With Preexisting Heart Failure: Management of Confounding Clinical Features.
Preexisting heart failure (HF) in patients with sepsis is associated with worse clinical outcomes. Core sepsis management includes aggressive volume resuscitation followed by vasopressors (and potentially inotropes) if fluid is inadequate to restore perfusion; however, large fluid boluses and vasoactive agents are concerning amid the cardiac dysfunction of HF. This review summarizes evidence regarding the influence of HF on sepsis clinical outcomes, pathophysiologic concerns, resuscitation targets, hemodynamic interventions, and adjunct management (ie, antiarrhythmics, positive pressure ventilatory support, and renal replacement therapy) in patients with sepsis and preexisting HF. Patients with sepsis and preexisting HF receive less fluid during resuscitation; however, evidence suggests traditional fluid resuscitation targets do not increase the risk of adverse events in HF patients with sepsis and likely improve outcomes. Norepinephrine remains the most well-supported vasopressor for patients with sepsis with preexisting HF, while dopamine may induce more cardiac adverse events. Dobutamine should be used cautiously given its generally detrimental effects but may have an application when combined with norepinephrine in patients with low cardiac output. Management of chronic HF medications warrants careful consideration for continuation or discontinuation upon development of sepsis, and β-blockers may be appropriate to continue in the absence of acute hemodynamic decompensation. Optimal management of atrial fibrillation may include β-blockers after acute hemodynamic stabilization as they have also shown independent benefits in sepsis. Positive pressure ventilatory support and renal replacement must be carefully monitored for effects on cardiac function when HF is present.


Central mechanism of action of antimigraine prophylactic drugs.
The pathogenesis of migraine is obscure. A hyperexcitable brain state has been postulated. Cortical spreading depression (CSD) is the most suggestive argument for the brain hyperexcitability. It has been showed that valproate, topiramate, amitriptyline and propranolol inhibit CSD in rats, which suggests that most preventative treatments of migraine act by normalising neuronal firing and increasing a genetically lowered and environmentally modified threshold for neuronal discharge. It has also been suggested that some antimigraine prophylactic drugs (i.e., amitriptyline, candesartan and magnesium) may act by restoring central nociceptive dysmodulation.


Expression of CK 19 as a biomarker in early detection of oral squamous cell carcinoma.
Increased mortality in oral squamous cell carcinoma (OSCC) had been attributed to delay in diagnosis. Lack of a specific marker to assess the malignant potential of premalignant lesions is thought to be one of the reasons for late detection. Expression of Cytokeratin 19, which is widely used as an odontogenic epithelial marker had been reported in OSCC. Downregulation of CK 19 expression plays an important role in terminal differentiation of superficial squamous cell and increased expression in various epithelial malignancies has been suggested to be an indicator of malignant change. To assess the role of CK19 as a potential marker in predicting malignant transformation in oral precancerous lesions and as a prognostic marker in OSCC. Study population consisted of ten samples each of normal oral mucosa, epithelial hyperplasia, varying grades of both oral epithelial dysplasias and OSCC. The tissue sections were subjected to immunohistochemical staining for the marker cytokeratin 19. An increased expression of CK19 was noted in oral epithelial hyperplasia, severe dysplasia and in superficial epithelium at the invading front in OSCC. In mild and moderate dysplasias, CK19 expression was lower than the normal mucosa. In oral squamous cell carcinoma, the expression of CK19 was restricted to either a few islands or a few cells within the islands, resulting in a lesser expression than the normal epithelium. The malignant epithelial islands in the superficial connective tissue stroma were showing greater expression than the deeper islands. The epithelial cells associated with formation of keratin pearls were found to be showing more expression than those with infrequent keratin pearls. The study suggests that malignant transformation of epithelium can be predicted based on the increased expression of CK19. But it should be done with caution as a similar increased expression may also be noticed in presence of inflammation.


Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes.
Viruses exploit different strategies to escape immune surveillance, including the introduction of mutations in cytotoxic T-lymphocyte (CTL) epitopes. The sequence of these epitopes is critical for their binding to major histocompatibility complex (MHC) class I molecules and recognition by specific CTLs, both of which interactions may be lost by mutation. Sequence analysis of the nucleoprotein gene of influenza A viruses (H3N2) isolated in The Netherlands from 1989 to 1999 revealed two independent amino acid mutations at the anchor residue of the HLA-B27-specific CTL epitope SRYWAIRTR (383 to 391). A R384K mutation was found in influenza A viruses isolated during the influenza season 1989-1990 but not in subsequent seasons. In the influenza season 1993-1994, a novel mutation in the same CTL epitope at the same position was introduced. This R384G mutation proved to be conserved in all influenza A viruses isolated from 1993 onwards. Both mutations R384K and R384G abrogated MHC class I presentation and allowed escape from recognition by specific CTLs.


Oral Lactulose vs. Polyethylene Glycol for Bowel Preparation in Colonoscopy: A Randomized Controlled Study.
Background Colonoscopy is the method of choice to evaluate colonic mucosa and the distal ileum, allowing the diagnosis and treatment of many diseases. Appropriate bowel preparation necessitates the use of laxative medications, preferentially by oral administration. These include polyethylene glycol (PEG), sodium picosulfate, and sodium phosphate (NaP). Lactulose, a semi-synthetic derivative of lactose, undergoes fermentation, acidifying the gut environment, stimulates intestinal motility, and increases osmotic pressure within the lumen of the colon. Methods In this prospective randomized controlled study, we analyzed 40 patients who presented with symptomatic bleeding per rectum and underwent bowel preparation either with lactulose or polyethylene glycol for colonoscopy. The quality of bowel preparation and other variables like palatability, discomfort, and electrolyte levels were analyzed. Results The majority of the patients (90%) were comfortable with the taste of lactulose solution, whereas the PEG group patients (55%) were equally divided on its palatability. On lactulose consumption, 40% of patients reported nausea/vomiting and around 10% of patients complained of abdominal discomfort. Serum sodium levels showed insignificant changes from 4.33 ± 0.07 mEq/L to 4.21 ± 0.18 mEq/L while potassium also remained similar from 4.26 ± 0.03 mEq/L to 4.22 ± 0.17 mEq/L. The mean Boston Bowel Preparation Score (BBPS) in patients who received lactulose solution was 6.25 ± 0.786 and in those who received PEG solution, it was 6.35 ± 0.813 (P-value = 0.59). Conclusions Lactulose is a significantly more palatable form of bowel preparation and causes minor discomfort. It has a good bowel cleansing action comparable to PEG without causing any hemodynamic changes. It can be considered a cheaper and safe alternative for bowel preparation in colonoscopy in low-resource settings.


[New developments in the problem of animal and human paragonimiasis].
A possibility of participation of reservoir hosts (mammals) in the biological cycle of trematodes of the genus Paragonimus, which has recently been experimentally proved, is discussed. A man can become infected with paragonimiasis not only through raw crawfishes and crabs but also through unboiled meat of some mammals. The authors found out that man can serve as a reservoir host of these trematodes too. The larval (muscular) form of paragonimiasis discovered by the authors was already recorded from over 100 patients. New species and subspecies of Paragonimus and their certain characters are reported.


Surgical outcomes and stoma-related complications in inflammatory bowel disease in Saudi Arabia: a retrospective study.
The prevalence of inflammatory bowel diseases (IBD), Crohn's (C) and ulcerative colitis (UC) has increased in Saudi Arabia during the past decade. Even though medical treatment is first-line therapy, most patients require surgery during the course of the disease. Stoma creation complications in IBD are underreported in the literature of the Middle East and especially in Saudi Arabia. Report the postoperative, stoma and peristomal complications following stoma creation in (C) versus UC. Retrospective cohort study. Tertiary care center. Patients with IBD who underwent stoma creation for either UC or CD between August 2015 and July 2020 were included. The diseases were compared to assess their characteristics and association to postoperative, stoma and peristomal complications. All complications were reported over a 90-day duration from the surgery. Patients younger than 14 years of age were excluded. Postoperative complications, stoma and peristomal complications in IBD patients who underwent stoma creation. 50. Of 50 IBD patients underwent stoma creation, 32 patients (64%) were diagnosed with CD and 18 patients (36%) with UC. Most of the procedures in both groups were laparoscopic and elective. Low BMI and serum albumin were more prevalent in the CD group. Postoperative complications were higher in the CD patients compared to the UC patients (CD 40.6% vs UC 11.1%, P=.028) with the most common complication being abdominal collection[a]. Stoma complications were comparable between the two groups (UC 16.7% vs CD 15.6%). However, peristomal complications were higher clinically in UC patients in comparison with the CD patients (UC 61.1% vs CD 37.5% P=.095) with the most common complication being skin excoriation (UC 44.4% vs CD 37.5%). CD has significantly higher postoperative complications compared to UC. Peristomal complications were high in both groups and had a negative impact on quality of life. Therefore, comprehensive stoma education and regular outpatient follow ups are recommended to improve the overall outcomes. Retrospective and conducted in one academic institution with a small sample size.


Fusion of face and speech data for person identity verification.
Biometric person identity authentication is gaining more and more attention. The authentication task performed by an expert is a binary classification problem: reject or accept identity claim. Combining experts, each based on a different modality (speech, face, fingerprint, etc.), increases the performance and robustness of identity authentication systems. In this context, a key issue is the fusion of the different experts for taking a final decision (i.e., accept or reject identity claim). We propose to evaluate different binary classification schemes (support vector machine, multilayer perceptron, C4.5 decision tree, Fisher's linear discriminant, Bayesian classifier) to carry on the fusion. The experimental results show that support vector machines and Bayesian classifier achieve almost the same performances, and both outperform the other evaluated classifiers.


Korean American Patients' and Family Caregivers' Sources of Social Support and Perceptions of Cancer and the Caregiving Role: A Theory-Driven Qualitative Study.
To understand the sources of social support and perceptions of cancer and the caregiving role for Korean American patients with cancer and their family caregivers. Using convenience sampling, Korean American patients with cancer and their family caregivers were recruited from Korean American churches and community health agencies. Semistructured interviews guided by the sociocultural stress and coping model were conducted with 12 dyads (N = 24) of Korean American patients with cancer and their family caregivers. Data were analyzed using thematic analysis. Patients' social support sources included Korean cancer support programs, family or friends, and religion. Family caregivers' sources of social support were limited to religion and friends. Nurses can encourage patients with cancer in racial and ethnic minority groups to attend cancer support programs offered in their primary language to enhance their quality of life during cancer survivorship. Culturally tailored interventions are needed to support the patients' family caregivers.


Free and total prostate specific antigen in benign prostate hyperplasia and prostate cancer.
To record the levels of PSA in the sera of prostate cancer (CaP) and benign prostatic hyperplasia (BPH) cases. Free PSA/total PSA as percentage was also calculated in order to evaluate its utility in differentially diagnosing BPH and CaP. A cross-sectional, case control study. Shaikh Zayed Hospital and Mayo Hospital, Lahore from August 2002 to March 2003. A group of 108 male subjects, including one-third of each of biopsy-confirmed prostate cancer cases, BPH cases and asymptomatic controls of matching age were studied. PSA and Free PSA were determined by ELISA using commercially available assay kits. Mean PSA was found to be highest in CaP cases (41.9 +/- 38.7 ng/ml), lower in the BPH cases (13.5 +/- 10.5 ng/ml), while it was lowest in the control subjects (5.7 +/- 4.4 ng/ml). Moreover, it was observed that a majority of the CaP cases had serum PSA >20 ng/ml, 50% of BPH cases had serum PSA in the 'gray zone' (4.1-20 ng/ml), while majority of controls had serum PSA in the 'normal' range (0 - 4 ng/ml). Using a free- PSA "cut-off" of 18% to differentiate between benign and malignant prostate enlargement, it was found that 80% of the CaP cases had F/T% <18, while 75% of the BPH cases had F/T%>18. The percent free-PSA test to differentially diagnose BPH and CaP in the 'gray zone' was found to have a sensitivity of 86% and a specificity of 94%. Using a cutoff of 18%, the free-PSA test significantly improved the differential diagnosis of BPH and CaP in the 'gray zone' as compared to the use of total PSA alone in the study group.


Mycobacterium bovis BCG immunization induces protective immunity against nine different Mycobacterium tuberculosis strains in mice.
Recent preclinical and epidemiologic studies have suggested that certain Mycobacterium tuberculosis genotypes (in particular, Beijing lineage strains) may be resistant to Mycobacterium bovis BCG vaccine-induced antituberculosis protective immunity. To investigate the strain specificity of BCG-induced protective responses in a murine model of pulmonary tuberculosis, C57BL/6 mice were vaccinated with BCG vaccine and then challenged 2 months later with one of nine M. tuberculosis isolates. Four of these strains were from the W-Beijing lineage (HN878, N4, NHN5, and ChS) while four were non-Beijing-type isolates (C913, CDC1551, NY669, and NY920). As a control, the WHO standard M. tuberculosis Erdman strain was evaluated in these vaccination/challenge experiments. To assess the protective responses evoked by BCG immunization, organ bacterial burdens and lung pathology were assessed in vaccinated and naïve mice at 4, 12, and 20 weeks postchallenge as well as during the day of infection. At 4 weeks after the aerosol challenge with each of these strains, significantly reduced bacterial growth in the lungs and spleens and significantly improved lung pathology were seen in all vaccinated animals compared to naïve controls. After 12 weeks, reduced organ bacterial burdens were detected in vaccinated animals infected with six of nine challenge strains. Although lung CFU values were lower in vaccinated mice for only three of nine groups at 20 weeks postchallenge, significantly decreased lung inflammation was seen in all immunized animals relative to controls at 20 weeks postchallenge. Taken together, these data demonstrate that BCG vaccination protects against infection with diverse M. tuberculosis strains in the mouse model of pulmonary tuberculosis and suggest that strain-specific resistance to BCG-induced protective immunity may be uncommon.


[Operative treatment and diagnostics of Zenker diverticulum using modern endoscopic technique].
The authors present results of examination and treatment of 272 patients with Zenker diverticulums of different localization. Features and problems in fibroesophagoscopy in patients with Zenker diverticulum are discussed. Surgical interventions with endoscopic assistance were fulfilled in 37 patients with diverticulum. A new way of endoscopic management of Zenker diverticulum using preparation "Disport" and the method of endoscopic incision of cricofaringeal muscle are proposed. Good clinical results of the treatment were obtained.


Managing the physics of the economics of integrated health care.
The physics metaphor, as applied to the economics (and financial performance) of the integrated health system, seems appropriate when considered together with the nine principles of management framework provided. The nature of the integrated design enhances leaders' management potential as they consider organizational operations and strategy in the markets ahead. One question begged by this argument for the integrated design is the durability, efficiency and ultimate long-term survivability of the more "traditional" community health care delivery models, which, by design, are fragmented, internally competitive and less capital efficient. They also cannot exploit the leverage of teams, optimal access management or the pursuit of revenues made available in many forms. For those who wish to move from the traditional to the more integrated community health system designs (especially those who have not yet started the journey), the path requires: * Sufficient balance sheet capacity to fund the integration process-especially as the model requires physician practice acquisitions and electronic health record implementations * A well-prepared board13, 14 * A functional, durable and sustainable physician services enterprise design * A redesigned organizational and governance structure * Favorable internal financial incentives alignment design * Effective accountable physician leadership * Awareness that the system is not solely a funding strategy for acquired physicians, rather a fully -.. committed clinical and business model, one in which patient-centered integrated care is the core service (and not acute care hospital-based services) A willingness to create and exploit the implied and inherent potential of an integrated design and unified brand Last, it's important to remember that an integrated health system is a tool that creates a "new potential" (a physics metaphor reference, one last time). The design doesn't operate itself. Application of the management principles presented here are necessary as a complete recipe. Leaders of health systems moving toward integration are cautioned to apply the recipe in full. This article ends with two questions. First, if not an integrated model of health care, what's the alternative? Since it seems clear that many of the existing community-based models are excessively fragmented and inefficient, especially in a reforming U.S. health care marketplace, is there a new model that is superior to the integrated models and, if so, what is it and what are its functional principles? The second question: Is there more than one functional form of integration? This article argues for the most integrated form. Others would argue that clinical integration is sufficient,'s and full integration isn't required. The stability, durability and adaptability of the fully integrated models have, arguably, been tested. The lesser integrated models remain to be proven in an unstable health care marketplace seeking higher levels of economic efficiency.


Sequence-dependent oligomerization of the Neu transmembrane domain suggests inhibition of "conformational switching" by an oncogenic mutant.
Membrane-spanning epidermal growth factor receptor ErbB2 is of key importance in cell division, in which a dimeric complex of the protein is responsible for tyrosine kinase activation following ligand binding. The rat homologue of this receptor (Neu) is prone to a valine to glutamic acid mutation in the transmembrane domain (TM), resulting in permanent activation and oncogenesis. In this study, the TM domains of Neu and the corresponding oncogenic mutant Neu*, which contains a V to E mutation at position 664 in the TM domain, have been analyzed to improve our understanding of the structural effects of the oncogenic V(664)E mutation. Building on previous work, we have focused here on understanding the sequence dependence of TM helix-helix interactions and any differences in behavior upon introduction of the V(664)E mutation. Using a variety of biochemical and biophysical methods, we find that the rat Neu TM domain forms strong oligomers and, similar to previous observations for the human ErbB2 TM domain, the oncogenic mutation results in a reduced level of self-association. Our data also strongly indicate that the proto-oncogenic Neu TM domain can adopt multiple (at least two) oligomeric conformations in the membrane, possibly corresponding to the active and inactive forms of the receptor, and can "switch" between the two. Further, the oncogenic Neu* mutant appears to inhibit this "conformational switching" of TM dimers, as we observe that dimerization of the Neu* TM domain in the Escherichia coli inner membrane strongly favors a single conformation stabilized by an IXXXV motif (I(659)-XXX-V(663)) originally identified by site-specific infrared spectroscopic studies.


Use of Conivaptan (Vaprisol) for hyponatremic neuro-ICU patients.
Hyponatremia is common in neurocritical care and is associated with poor outcome, but the optimal treatment is not known. We wished to test the hypothesis that for neurocritical care patients with severe hyponatremia (Na < 130 mmol/l) or hyponatremia (Na < 135 mmol/l) with depressed Glasgow Coma Scale (GCS) that conivaptan use would lead to increased serum sodium compared to usual care. We prospectively screened 249 neurocritical care patients with hyponatremia for a prospective, randomized pilot (goal N = 20) trial. Study interventions were usual care, or usual care plus conivaptan 20 mg IV as a bolus followed by 20 mg IV over 24 h, the lower FDA-approved dose. Patients were prospectively followed for changes in serum and urine electrolytes and clinical examinations with a blinded examiner. This study is registered at www.clinicaltrials.gov (NCT00727090). Despite the prevalence of hyponatremia, recruitment was difficult, and the study was terminated after six patients were enrolled, three in each group. Most hyponatremia in screened but non-randomized patients was transient or not associated with depressed GCS. Conivaptan led to higher serum sodium compared to usual care. The change in serum sodium from baseline, the pre-specified endpoint, was significantly different between groups at six (7.0 +/- 1.7 vs. -0.6 +/- 2.1 mmol/l, P = 0.008), 24 (9.7 +/- 3.2 vs. 0 +/- 1.0 mmol/l), and 36 h (8.0 +/- 5.6 vs. -1.7 +/- 2.1 mmol/l, P = 0.05). There were no apparent differences in clinical examination as a result of treatment. Adverse events were similar, and all randomized patients completed the protocol. Despite an inclusive protocol, most patients were not candidates for conivaptan therapy for hyponatremia. The role of conivaptan in the Neuro-ICU remains to be defined.


Effects of HiBalance training program on physical function of individuals with idiopathic Parkinson disease: a systematic review and meta-analysis.
The effectiveness of the HiBalance training program for individuals with Parkinson disease (PD) remains debated, prompting a systematic investigation. This study aims to assess whether the HiBalance training program yields favorable outcomes on physical function and self-reported function measures in PD individuals. A systematic search across PubMed, Cochrane Library, Ovid, Scopus, and PEDro databases identified studies exploring HiBalance training's impact on physical function in idiopathic PD. Publication date restrictions were not applied. Two independent reviewers evaluated bias risk using the Cochrane Risk of Bias tool and study quality using the PEDro scale. Effect size (standardized mean difference, SMD) and heterogeneity (Higgins I2) were determined. Six studies underwent qualitative analysis, with two randomized-controlled trials and one multi-center clinical trial being included in the meta-analysis. HiBalance training exhibited a significant impact on physical function (SMD = 0.49; P = 0.0003). The Mini-BESTest score and gait velocity displayed improvements with moderate-effect sizes. However, solely gait velocity showed clinical enhancement. Yet, these benefits did not remain at the 6- and 12-month follow-ups post-intervention. Self-reported function measures showed no alteration post-HiBalance training. Publication bias was absent. HiBalance training led to clinically significant improvements solely in gait velocity, though these gains waned over time. The findings suggest the necessity of refining the HiBalance program to sustain positive outcomes and ensure lasting enhancements. This underscores the importance of post-HiBalance training exercise programs to maintain benefits in the long term. The protocol of this review and meta-analysis was registered at PROSPERO (CRD42022325649). Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022325649 .


Conformational assignment of gas phase peptides and their H-bonded complexes using far-IR/THz: IR-UV ion dip experiment, DFT-MD spectroscopy, and graph theory for mode assignment.
The combined approach of gas phase IR-UV ion dip spectroscopy experiments and DFT-based molecular dynamics simulations for theoretical spectroscopy reveals the 3D structures of (Ac-Phe-OMe)1,2 peptides using their far-IR/THz signatures. Both experimental and simulated IR spectra are well-resolved in the 100-800 cm-1 domain, allowing an unambiguous assignment of the conformers, that could not be achieved in other more congested spectral domains. We also present and make proofs-of-principles for our newly developed theoretical method for the assignment of (anharmonic) vibrational modes from MD simulations based on graph theory coupled to APT-weighted internal coordinates velocities DOS spectra. The principles of the method are reviewed, applications to the simple gas phase water and NMA (N-methyl-acetamide) molecules are presented, and application to the more complex (Ac-Phe-OMe)1,2 peptidic systems shows that the complexity in assigning vibrational modes from MD simulations is reduced with the graphs. Our newly developed graph-based methodology is furthermore shown to allow an easy comparison between the vibrational modes of isolated monomer(s) and their complexes, as illustrated by the (Ac-Phe-OMe)1,2 peptides.


Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.
Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study. Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.


Intra-Venous Lidocaine to Relieve Neuropathic Pain: A Systematic Review and Meta-Analysis.
Background: The prevalence of neuropathic pain is estimated to be between 7 and 10% in the general population. The efficacy of intravenous (IV) lidocaine has been studied by numerous clinical trials on patients with neuropathic pain. The aim of this systematic review and meta-analysis was to evaluate the efficacy of IV lidocaine compared with a placebo for neuropathic pain and secondly to assess the safety of its administration. Methods: A literature search on PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google scholar databases was performed for relevant studies published up to February 2019. Randomized controlled trials (RCTs) evaluating IV lidocaine treatment for pain relief in patients with neuropathic pain were included. Results: 26 articles met the inclusion criteria. Patients with varied etiology of neuropathic pain were among the patient samples of these studies. Fifteen articles were included for quantitative analysis. Lidocaine was superior to a placebo in relieving neuropathic pain in the early post-infusion period [Mean Difference (MD) = -11.9; 95% Confidence interval (CI): -16.8 to -7; p < 0.00001]. Multiple infusions of lidocaine over a period of 4 weeks, however, had no significant effect on reliving neuropathic pain (MD = -0.96; 95% CI: -2.02 to 0.11; p = 0.08). IV lidocaine was also associated with a significant number of adverse events compared to a placebo [Odds Ratio (OR) = 7.75; 95% CI: 3.18-18.92; p < 0.00001]. Conclusion: Our study indicates that while IV lidocaine is effective in pain control among patients with neuropathic pain in the immediate post-infusion period, it does not have a long-lasting, persistent effect. IV infusions of the drug are associated with an increased risk of side effects compared to a placebo. However, the risk of serious adverse events is negligible. Further, well-designed RCTs evaluating the effects of various dosages and infusion periods of IV lidocaine are required to provide clear guidelines on its clinical use.


Comparison of Food Intake Among Infants and Toddlers Participating in a South Central Texas WIC Program Reveals Some Improvements After WIC Package Changes.
In 2009, WIC began issuing revised food packages with the intent of improving dietary practices such as breastfeeding, delaying the introduction of complementary foods until about 6 months, limiting juice intake, and increasing intake of fruits, vegetables, whole grains, and baby food meats as appropriate for age. This observational study investigated whether dietary intake and feeding practices of a sample of majority-Hispanic infants and toddlers participating in a WIC clinic in south central Texas improved after the package changes. Feeding practices data and 24-h recalls were collected during telephone interviews with 84 caregivers of infants (4-12 months) and toddlers (1-2 years) in 2009 before the package change and with 112 caregivers in 2011 after the package change. The Nutrition Data System for Research was used to collect 24-h recalls. Outcomes for the two study years were compared using Chi square analysis for categorical and Mann-Whitney U analysis for continuous variables. Breastfeeding initiation, breastfeeding duration, age of introduction of complementary foods, and exposures to baby food fruits, vegetables, and meats among infants did not improve after the package changes. Significantly fewer infants received cereal in their bottles and fewer toddlers consumed vegetables and eggs after the package changes. The observed feeding practices of infants and toddlers among this sample did not reflect the WIC package changes. Strategic and comprehensive breastfeeding and nutrition education are recommended. Package modifications such as adding eggs back to the toddler package and allowing more flexibility for purchasing fresh produce and baby foods may be warranted.


First record of epizootic ulcerative syndrome from the Upper Congo catchment: An outbreak in the Bangweulu swamps, Zambia.
We report on the first outbreak of epizootic ulcerative syndrome (EUS) amongst wild fish populations in the Bangweulu swamps, an inland delta, in the north of Zambia during 2014. The area supports a large and diverse fish fauna related to, but distinct from, that of the Zambezi River system where EUS outbreaks have occurred since 2006. A sizeable artisanal fishery, based on extensive fish weirs, is sustained by the annual flooding of the swamps, and observations of the disease outbreak by fishermen were recorded. Signs typical of infection with Aphanomyces invadans were observed in a number of species. Clinical observations, histology and molecular diagnostic methods were used to confirm infection with A. invadans in two of the most commonly and severely affected species. Several features of the wetland may have contributed to the outbreak and the annual recurrence of the disease. Modes by which the disease may have been introduced into the swamps are discussed. The outbreak is of great significance as the Bangweulu swamps drain into the Congo River in neighbouring Democratic Republic of Congo, Africa's largest drainage system with an extensive and diverse fish fauna previously unaffected by EUS.


The Brazilian national prospective active surveillance (AS) cohort of patients with low-risk prostate cancer in the public health system: vigiaSUS study protocol.
Prostate cancer exhibits a very diverse behaviour, with some patients dying from the disease and others never needing treatment. Active surveillance (AS) consists of periodic PSA assessment (prostate-specific antigen), DRE (digital rectal examination) and periodic prostate biopsies. According to the main guidelines, AS is the preferred strategy for low-risk patients, to avoid or delay definitive treatment. However, concerns remain regarding its applicability in certain patient subgroups, such as African American men, who were underrepresented in the main cohorts. Brazil has a very racially diverse population, with 56.1% self-reporting as brown or black. The aim of this study is to evaluate and validate the AS strategy in low-risk prostate cancer patients following an AS protocol in the Brazilian public health system. This is a multicentre AS prospective cohort study that will include 200 patients from all regions of Brazil in the public health system. Patients with prostate adenocarcinoma and low-risk criteria, defined as clinical staging T1-T2a, Gleason score ≤ 6, and PSA < 10 ng/ml, will be enrolled. Archival prostate cancer tissue will be centrally reviewed. Patients enrolled in the study will follow the AS strategy, which involves PSA and physical examination every 6 months as well as multiparametric MRI (mpMRI) every two years and prostate biopsy at month 12 and then every two years. The primary objective is to evaluate the reclassification rate at 12 months, and secondary objectives include determining the treatment-free survival rate, metastasis-free survival, and specific and overall survival. Exploratory objectives include the evaluation of quality of life and anxiety, the impact of PTEN loss and the economic impact of AS on the Brazilian public health system. This is the first Brazilian prospective study of patients with low-risk prostate cancer under AS. To our knowledge, this is one of the largest AS study cohort with a majority of nonwhite patients. We believe that this study is an opportunity to better understand the outcomes of AS in populations underrepresented in studies. Based on these data, an AS national clinical guideline will be developed, which may have a beneficial impact on the quality of life of patients and on public health. Clinicaltrials registration is NCT05343936.


Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis.
Background: Acidic microenvironment is a common physiological phenomenon in tumors, and is closely related to cancer development, but the effects of acidosis on pancreatic adenocarcinoma (PDAC) remains to be elucidated. Methods: Metabonomic assay and transcriptomic microarray were used to detect the changes of metabolites and gene expression profile respectively in acidosis-adapted PDAC cells. Wound healing, transwell and in vivo assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation assays were performed to determine cell proliferation. Results: The acidosis-adapted PDAC cells had stronger metastasis and proliferation ability compared with the control cells. Metabonomic analysis showed that acidosis-adapted PDAC cells had both increased glucose and decreased glycolysis, implying a shift to pentose phosphate pathway. The metabolic shift further led to the inactivation of AMPK by elevating ATP. Transcriptomic analysis revealed that the differentially expressed genes in acidosis-adapted cells were enriched in extracellular matrix modification and Hippo signaling. Besides, MMP1 was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway, but could be reduced by AMPK activator. Conclusion: The present study showed that metabolic reprogramming promotes proliferation and metastasis of acidosis-adapted PDAC cells by inhibiting AMPK/Hippo signaling, thus upregulating MMP1.


LEPTOSPIRA SPECIES STATUS OF CAPTIVE NONHUMAN PRIMATES AND FREE-RANGING RODENTS AT THE BARRANQUILLA ZOO, COLOMBIA, 2013.
Leptospirosis is a zoonotic disease with worldwide distribution caused by pathogenic Leptospira spp. Pathogenic Leptospira spp. are shed in urine of infected hosts and transmitted via ingestion of contaminated food or water, inoculation, inhalation of aerosolized urine, and absorption through mucous membranes. Leptospirosis is of particular concern in tropical and subtropical regions such as Barranquilla, Colombia. Recent reports indicate that in Barranquilla, rodents, dogs, and humans have a high leptospiral seroprevalence; and amongst zoo mammals, nonhuman primates have a high prevalence of Leptospira spp. infection. We therefore sought to determine whether primates in captivity at the Barranquilla Zoo were exposed to Leptospira spp. and whether there was a probable causal transmission link between the primates and peridomestic rodents. Samples were collected from 29 captive nonhuman primates, 15 free-ranging rats (Rattus rattus), and 10 free-ranging squirrels (Sciurus granatensis). Serum samples from primates, rats, and squirrels were evaluated via microagglutination test (MAT) vs 24 reference Leptospira serovars. Blood and urine from the primates and kidney tissue from the rats and squirrels were cultured in Ellinghausen-McCullough-Johnson-Harris (EMJH) medium and polymerase chain reaction (PCR) of lipL32 was performed to determine whether active infection was present. Leptospiral seroprevalence was found to be 66.7% (10/15) in rats, 60% (6/10) in squirrels, and 6.9% (2/29) in neotropical primates. Ateles hybridus and Ateles fusciceps had positive titers to serogroups Cynopteri and Ictohaemorrhagiae, respectively. Of the rodents that had antibodies against Leptospira spp., 90% of the rats and 66.7% of the squirrels corresponded to the serovar australis. Interestingly, all animals were culture and PCR negative, indicating Leptospira spp. exposure in the absence of current infection. While their status as maintenance hosts needs to be investigated further, this is the first study to show leptospiral seropositivity in red-tailed squirrels (S. granatensis).


Associations between Sugar Intake from Different Food Sources and Adiposity or Cardio-Metabolic Risk in Childhood and Adolescence: The Korean Child-Adolescent Cohort Study.
The increasing prevalence of childhood obesity is a serious public health problem associated with co-morbidities in adulthood, as well as childhood. This study was conducted to identify associations between total sugar intake and sugar intake from different foods (fruit, milk, and sugar-sweetened beverages (SSBs)), and adiposity and continuous metabolic syndrome scores (cMetS) among Korean children and adolescents using cohort data. The study subjects were children (n = 770) who participated in the 4th year (2008) of the Korean Child-Adolescent Cohort Study (KoCAS). Dietary intake data were collected via three-day 24-h food records, and sugar intake was calculated for the total sugar content of foods using our database compiled from various sources. Anthropometric measurements, assessments of body composition, and blood sample analysis were performed at baseline and at follow-up four years later. The cMetS was calculated based on waist circumference, triglycerides, high-density lipoprotein cholesterol, glucose, and mean arterial blood pressure. According to multiple linear regression analysis, there were no significant associations between total sugar intake and adiposity and cMetS. However, higher intake of fruit sugar at baseline was significantly associated with lower body mass index (BMI) z-scores and body fat percentages at baseline (β = -0.10, p = 0.02 and β = -0.78, p < 0.01, respectively). At follow-up, sugar intake from fruit at baseline was still negatively associated with the above outcomes, but only the relationship with BMI z-scores retained statistical significance (β = -0.08, p < 0.05). There was a significant positive relationship between consumption of sugar from SSBs and cMetS at baseline (β = 0.04, p = 0.02), but that relationship was not observed at follow-up (p = 0.83). Differences in consumption sugars from fruit and SSBs might play an important role in the risk of adiposity and metabolic disease in children and adolescents. Our results suggest that strategies for reducing sugar intake need to target particular food groups. Consequently, this information could be of value to obesity- and metabolic disease-prevention strategies.


How I treat relapsed acute lymphoblastic leukemia in the pediatric population.
Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis. Although there have been some improvements in outcomes over the past few decades, only ∼50% of children with first relapse of ALL survive long term, and outcomes are much worse with second or later relapses. Recurrences that occur within 3 years of diagnosis and any T-ALL relapses are particularly difficult to salvage. Until recently, treatment options were limited to intensive cytotoxic chemotherapy with or without site-directed radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). In the past decade, several promising immunotherapeutics have been developed, changing the treatment landscape for children with relapsed ALL. Current research in this field is focusing on how to best incorporate immunotherapeutics into salvage regimens and investigate long-term survival and side effects, and when these might replace HSCT. As more knowledge is gained about the biology of relapse through comprehensive genomic profiling, incorporation of molecularly targeted therapies is another area of active investigation. These advances in treatment offer real promise for less toxic and more effective therapy for children with relapsed ALL, and we present several cases highlighting contemporary treatment decision-making.


Ultrasonic Assessment of Myocardial Microstructure in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy.
The noninvasive assessment of altered myocardium in patients with genetic mutations that are associated with hypertrophic cardiomyopathy (HCM) remains challenging. In this pilot study, we evaluated whether a novel echocardiography-based assessment of myocardial microstructure, the signal intensity coefficient (SIC), could detect tissue-level alterations in HCM sarcomere mutation carriers with and without left ventricular hypertrophy. We studied 3 groups of genotyped individuals: sarcomere mutation carriers with left ventricular hypertrophy (clinical HCM; n=36), mutation carriers with normal left ventricular wall thickness (subclinical HCM; n=28), and healthy controls (n=10). We compared measurements of echocardiographic SIC with validated assessments of cardiac microstructural alteration, including cardiac magnetic resonance measures of interstitial fibrosis (extracellular volume fraction), as well as serum biomarkers (NTproBNP, hs-cTnI, and PICP). In age-, sex-, and familial relation-adjusted analyses, the SIC was quantitatively different across subjects with overt HCM, subclinical HCM, and healthy controls (P<0.001). Compared with controls, the SIC was 61% higher in overt HCM and 47% higher in subclinical HCM (P<0.001 for both). The SIC was significantly correlated with extracellular volume (r=0.72; P<0.01), with left ventricular mass and E' velocity (r=0.45, -0.60, respectively; P<0.01 for both), and with serum NTproBNP levels (r=0.36; P<0.001). Our findings suggest that the SIC could serve as a noninvasive quantitative tool for assessing altered myocardial tissue characteristics in patients with genetic mutations associated with HCM. Further studies are needed to determine whether the SIC could be used to identify subclinical changes in patients at risk for HCM and to evaluate the effects of interventions.


Analysis of protein-small molecule interactions by microscale equilibrium dialysis and its application as a secondary confirmation method for on-bead screening.
On-bead screening of one-bead one compound (OBOC) libraries is an ultra fast surface based primary high-throughput screening (HTS) method. Typically the binding of a tagged target protein to bead immobilized compounds or its altered enzymatic activity are detected. For an efficient and reliable ligand discovery process secondary assays to confirm on-bead compound activity in homogeneous solution are key to exclude artifacts and weak binders. Ideally they should allow to flag hit compounds with undesirable biophysical properties such as aggregation, unspecific binding, or insufficient solubility and the like. Here we demonstrate that miniaturized and parallelized equilibrium dialysis is an excellent and generic secondary confirmation method for hit compounds identified by on-bead screening. We further show that microscale dialysis can be reliably performed prior to decoding and resynthesis even with hit-compounds cleaved from the single beads. Down-scaling of the method takes advantage of the fluorescent tag, AIDA, which is integrated as permanent tracer in our library design. Our results suggest that microscale equilibrium dialysis followed by high performance liquid chromatography (HPLC) analysis is a generic, cheap, and meaningful confirmation method for identifying the most promising candidates within a series hit compounds derived from fluorescently tagged one-bead one-compound libraries.


Reduced brain/serum glucose ratios predict cerebral metabolic distress and mortality after severe brain injury.
The brain is dependent on glucose to meet its energy demands. We sought to evaluate the potential importance of impaired glucose transport by assessing the relationship between brain/serum glucose ratios, cerebral metabolic distress, and mortality after severe brain injury. We studied 46 consecutive comatose patients with subarachnoid or intracerebral hemorrhage, traumatic brain injury, or cardiac arrest who underwent cerebral microdialysis and intracranial pressure monitoring. Continuous insulin infusion was used to maintain target serum glucose levels of 80-120 mg/dL (4.4-6.7 mmol/L). General linear models of logistic function utilizing generalized estimating equations were used to relate predictors of cerebral metabolic distress (defined as a lactate/pyruvate ratio [LPR] ≥ 40) and mortality. A total of 5,187 neuromonitoring hours over 300 days were analyzed. Mean serum glucose was 133 mg/dL (7.4 mmol/L). The median brain/serum glucose ratio, calculated hourly, was substantially lower (0.12) than the expected normal ratio of 0.40 (brain 2.0 and serum 5.0 mmol/L). In addition to low cerebral perfusion pressure (P = 0.05) and baseline Glasgow Coma Scale score (P < 0.0001), brain/serum glucose ratios below the median of 0.12 were independently associated with an increased risk of metabolic distress (adjusted OR = 1.4 [1.2-1.7], P < 0.001). Low brain/serum glucose ratios were also independently associated with in-hospital mortality (adjusted OR = 6.7 [1.2-38.9], P < 0.03) in addition to Glasgow Coma Scale scores (P = 0.029). Reduced brain/serum glucose ratios, consistent with impaired glucose transport across the blood brain barrier, are associated with cerebral metabolic distress and increased mortality after severe brain injury.


Study of diagnostic accuracy of Helmintex, Kato-Katz, and POC-CCA methods for diagnosing intestinal schistosomiasis in Candeal, a low intensity transmission area in northeastern Brazil.
Control initiatives have successfully reduced the prevalence and intensity of schistosomiasis transmission in several localities around the world. However, individuals that release low numbers of eggs in their feces may not be detected by classical methods that are limited by low sensitivity. Given that accurate estimates of prevalence are key to implementing planning control actions for the elimination of schistosomiasis, new diagnostic tools are needed to effectively monitor infections and confirm transmission interruption. The World Health Organization recommends the Kato-Katz (KK) thick smear as a parasitological test for epidemiological surveys, even though this method has been demonstrated to underestimate prevalence when egg burdens are low. The point-of-care immunodiagnostic for detecting schistosome cathodic circulating antigen (POC-CCA) method has been proposed as a more sensitive substitute for KK in prevalence estimations. An alternative diagnostic, the Helmintex (HTX) method, isolates eggs from fecal samples with the use of paramagnetic particles in a magnetic field. Here, a population-based study involving 461 individuals from Candeal, Sergipe State, Brazil, was conducted to evaluate these three methods comparatively by latent class analysis (LCA). The prevalence of schistosomiasis mansoni was determined to be 71% with POC-CCA, 40.% with HTX and 11% with KK. Most of the egg burdens of the individuals tested (70%) were < 1 epg, thereby revealing a dissociation between prevalence and intensity in this locality. Therefore, the present results confirm that the HTX method is a highly sensitive egg detection procedure and support its use as a reference method for diagnosing intestinal schistosomiasis and for comparative evaluation of other tests.


Improving cancer incidence estimates for American Indians in Minnesota.
The purpose of this study was to estimate cancer incidence for American Indians in Minnesota. Indian Health Service enrollment data were linked to the Minnesota tumor registry to identify cancers among American Indians in Minnesota. Incidence rates for the 5 most common cancers in this population, estimated after the linkage, were compared with rates estimated before the linkage and with rates for the total population of Minnesota. The linkage identified 302 cancer cases not previously identified as occurring among American Indians in Minnesota. Postlinkage estimates suggested that incidence rates for prostate and colorectal cancer are similar to those for the total population of Minnesota, but that rates of lung and cervical cancer are significantly higher. Breast cancer rates are slightly lower than those for the total population of Minnesota but more than twice as high as previous estimates for American Indians. The postlinkage estimates suggest different priorities for cancer education, prevention, and control than might be assumed from either prelinkage estimates or previously published data, and underscore the importance of using accurate and specific data for setting these priorities.