O-linked sialic acid residues on platelet membrane glycoprotein IIb mask the human HPA-9b alloepitope.
Sialic acids occupy the terminal position of glycan chains and have the potential to influence the antigenicity of glycoproteins (GP). The polymorphisms of human platelet alloantigens (HPA)-3 and HPA-9, located near the C-terminus of the extracellular domain of platelet membrane GPIIb, are adjacent to sialyl-core 1 O-glycans emanating from serines 845 and 847. Whether the nearby O-glycans affect the antigenicity of HPA-9b or influence the binding of anti-HPA-9b alloantibodies in clinically significant cases of neonatal alloimmune thrombocytopenia is unknown. To address this issue, we generated a series of O-glycan mutant HPA-9 allele-specific induced pluripotent stem cell lines, differentiated them to megakaryocytes (MKs), and examined their ability to bind HPA-9b-specific alloantibodies. We found that both wild-type MKs treated with neuraminidase and those genetically modified to lack the sialidases ST3GAL1 and ST3GAL2 dramatically increased anti-HPA-9b alloantibody binding, indicating that the HPA-9b epitope is partially masked by terminal sialic acids on nearby O-glycans of GPIIb. Interestingly, mutating the serine residues that carry these glycan chains to alanine actually reduced the binding of anti-HPA-9b alloantibodies, indicating that these 2 O-glycan chains contribute to the presentation of the HPA-9b epitope-perhaps by stabilizing the conformation of the GP in this region. Collectively, our data suggest that detection of anti-HPA-9b alloantibodies may be enhanced through the use of HPA-9b-specific MKs that have been genetically altered to lack nearby terminal sialic acid residues but retain the glycan chains to which they are attached.


A multicentre review of the direct-access mammography programme in Ireland for women with breast pain.
To assess the current use of the direct access mammography pathway for breast pain and the rate of breast cancer detection in this patient cohort. A retrospective review of general practitioner (GP)-referred mammograms performed during a 12-month period from January to December 2022 across four tertiary referral centres. With the use of medical records and GP referrals, patient demographics, presenting symptoms, family history, and clinical outcomes were recorded. The present study comprised 2,046 patients of which 21.6% did not report breast pain at the time of referral. Thirty-five per cent had a positive family history with 40% of these patients having no breast pain. Twelve per cent were recalled with 30% of these patients requiring biopsy. An overall cancer detection rate (CDR) of 5.8 per 1000 was determined for women with mastalgia. A CDR of 0 per 1,000 was determined for women <50 years with mastalgia alone and no additional risk factors for malignancy. Fisher's exact test showed no statistically significant association between breast pain and breast cancer. There was no statistically significant relationship found between breast pain and breast cancer. This review suggests a low cancer detection rate in women <50 years. In women <50 years with mastalgia without additional symptoms or family history, breast imaging is not required.


Interaction among Btn1p, Btn2p, and Ist2p reveals potential interplay among the vacuole, amino acid levels, and ion homeostasis in the yeast Saccharomyces cerevisiae.
Btn2p, a novel cytosolic coiled-coil protein in Saccharomyces cerevisiae, was previously shown to interact with and to be necessary for the correct localization of Rhb1p, a regulator of arginine uptake, and Yif1p, a Golgi protein. We now report the biochemical and physical interactions of Btn2p with Ist2p, a plasma membrane protein that is thought to have a function in salt tolerance. A deletion in Btn2p (btn2Delta strains) results in a failure to correctly localize Ist2p, and strains lacking Btn2p and Ist2p (btn2Delta ist2Delta strains) are unable to grow in the presence of 0.5 or 1.0 M NaCl. Btn2p was originally identified as being up-regulated in a btn1Delta strain, which lacks the vacuolar-lysosomal membrane protein, Btn1p, and serves as a model for Batten disease. This up-regulation of Btn2p was shown to contribute to the maintenance of a stable vacuolar pH in the btn1Delta strain. Btn1p was subsequently shown to be required for the optimal transport of arginine into the vacuole. Interestingly, btn1Delta ist2Delta strains are also unable to grow in the presence of 0.5 or 1.0 M NaCl, and ist2Delta suppresses the vacuolar arginine transport defect in btn1Delta strains. Although further investigation is required, we speculate that altered vacuolar arginine transport in btn1Delta strains represents a mechanism for maintaining or balancing cellular ion homeostasis. Btn2p interacts with at least three proteins that are seemingly involved in different biological functions in different subcellular locations. Due to these multiple interactions, we conclude that Btn2p may play a regulatory role across the cell in response to alterations in the intracellular environment that may be caused by changes in amino acid levels or pH, a disruption in protein trafficking, or imbalances in ion homeostasis resulting from either genetic or environmental manipulation.


O-arylation versus C-arylation: copper-catalyzed intramolecular coupling of aryl bromides with 1,3-dicarbonyls.
The copper-catalyzed intramolecular coupling of aryl bromides with 1,3-dicarbonyls via a six-membered ring closure was examined. With CuI (10 mol %) as the catalyst, N,N'-dimethylethylenediamine as the ligand, and Cs2CO3 as the base, the reactions of alpha-(2-bromobenzyl)-beta-keto esters in THF at refluxing temperature afforded the corresponding substituted 4H-1-benzopyrans in high yields via O-arylation. On the other hand, the reactions of delta-(2-bromophenyl)-beta-keto esters in refluxing dioxane led to the formation of 3,4-dihydronaphthalen-2(1H)-one derivatives via C-arylation.


The penetration of serum albumin into phospholipid monolayers of different fatty acid chain length and interfacial charge.
1. The highest surface pressure of phosphatidylcholine monolayers allowing penetration of delipidated serum albumin decreased in the order dibehenoyl>distearoyl>dipalmitoyl=dimyristoyl. This pressure was not related to the area occupied or to the space available between the phospholipid molecules at the interface. 2. Penetration of albumin into yeast phosphatidylcholine monolayers was increased by adding a small percentage of long-chain anions (phosphatidic acid, dicetylphosphoric acid) to the film but only when the protein was below its isoelectric point (i.e. positively charged). 3. Stearylamine added to phosphatidylcholine monolayers had no effect on albumin penetration even when the protein was oppositely charged to that of the phospholipid/water interface. 4. The results are discussed in relation to the activation of certain phospholipases by anionic amphipathic substances.


Quality of life in patients with chronic heart failure and their carers: a 3-year follow-up study assessing hospitalization and mortality.
Chronic heart failure (CHF) due to left ventricular systolic dysfunction is associated with poor quality of life (QoL). This study aimed to assess factors affecting health-related QoL in CHF patients and their carers and the impact of QoL on clinical outcomes. Demographic, social, and clinical data were collected for consecutive CHF patients in an academic hospital setting. All patients (n = 179) and informal carers (n = 131) completed a generic QoL questionnaire (EQ-5D) and patients also completed a CHF-specific QoL questionnaire (Minnesota Living with Heart Failure Questionnaire, MLHFQ). Patients were then followed up for 3 years to assess subsequent hospitalizations and mortality. Minnesota Living with Heart Failure Questionnaire score was independently predicted by NYHA class, socioeconomic deprivation and lack of an informal carer. Severity of heart failure, anaemia, and cancer co-morbidity in CHF patients were associated with poor QoL in carers. Chronic heart failure patients with poor baseline QoL (MLHFQ > median) were at increased risk of hospital admissions [hazard ratios (HR) 7.3, P < 0.001] and death (HR 1.5, P = 0.09). Mortality was also independently associated with repeat hospitalization (HR 6.0, P < 0.001) and lack of beta-blocker therapy (HR 1.8, P = 0.03). Severe heart failure, poor socioeconomic status and lack of social support results in poor QoL in CHF patients which in turn leads to an increased risk of hospital admissions and death. Quality of life in carers is lower in female carers, those with socioeconomic deprivation and those caring for patients with higher NYHA class or having a cancer. Quality of life assessment may complement clinical prognostic markers to identify CHF patients at high risk of adverse events.


Patient safety as perceived by Swedish leaders.
The purpose of this paper is to survey Swedish healthcare leaders' patient safety awareness, the priority they give to safety issues and their views on suitable safety management strategies. A total 623 leaders of a sample of 1,129 responded to a mail questionnaire (55 percent response rate). Descriptive statistics of the responses are presented as frequency distributions across respondent subgroups. Means were tested for similarity by a repetitive one-way ANOVA procedure. Homogeneous response groups were sought by hierarchical cluster analysis. Swedish healthcare leaders show relatively high safety awareness and how their organizations prioritize safety management. There is a marked polarization between leaders; half feel that the system works reasonably well, and that adequate funds are available to improve or maintain services. The other half thinks the system needs major change and calls for additional funding. A majority sees system errors as the main cause for adverse events; a substantial minority find human errors to be more important. Two-thirds were willing to make safety performance information on organizations and specialties public, one third was restrictive. Survey instruments used to explore leaders' patient safety views have not yet been rigorously tested against psychometric criteria. One hospital type was slightly over-represented and three regions somewhat under-represented in the respondent groups. This is the first systematic attempt to explore the views of Swedish healthcare leaders on patient safety. It provides input to a national strategy to improve patient safety.


The influenza virus variant A/FM/1/47-MA possesses single amino acid replacements in the hemagglutinin, controlling virulence, and in the matrix protein, controlling virulence as well as growth.
Genetic analysis of mouse-adapted influenza virus variant A/FM/1/47 (FM) MA has previously identified four genome segments, 4, 5, 7, and 8, that are statistically associated with virulence. On sequencing these genome segments, we found single amino acid replacements at amino acid 47 of the HA2 subunit of the hemagglutinin and at amino acid 139 of the matrix protein. Mutation was not detected in segments 5 and 8, obviating a role for these genes in FM-MA virulence. FM-MA replicates to higher titer than FM in MDCK cells and in mouse lung. FM X FM-MA reassortants were used to show that the M1 gene controlled replication in MDCK cells as well as in mouse lung.


Experiences and Perspectives of Marketing Authorisation Holders towards Medication Safety Monitoring during Pregnancy: A Pan-European Qualitative Analysis.
Although marketing authorisation holders (MAHs) are involved in monitoring medication safety, it was unclear how they experience their role and current monitoring activities in pregnancy. Therefore, a qualitative study using online focus groups with MAHs and the Belgian umbrella organisation of MAHs was conducted in June-July 2021. In total, 38 representatives of nine organisations participated. Overall, participants reported multiple difficulties with data collection, including underreporting, collection of incomplete information, and loss to follow-up. The limited number of high-quality data collected, the unknown denominator and the lack of comparator data complicate MAHs' data processing activities, preventing them to timely provide evidence in the pregnancy label. Three 'conflicts' inherent to the specific position of MAHs were identified explaining the difficulties they experience, i.e., (1) mistrust from patients and healthcare professionals (HCPs); (2) MAHs' legal obligations and regulatory framework; (3) MAHs' position outside the healthcare context. To overcome these barriers, MAHs suggested that data registration should occur in close collaboration with patients and HCPs, organised within the healthcare context and performed by using a user-friendly system. In conclusion, the reported difficulties and underlying conflicts of MAHs highlight the need for more effective, collaborative data collection strategies to generate new evidence on this topic.


Recommended first-line management of asymptomatic brain metastases from EGFR mutant and ALK positive non-small cell lung cancer varies significantly according to specialty: an international survey of clinical practice.
The role for radiotherapy or surgery in the upfront management of brain metastases (BrM) in epidermal growth factor receptor mutant (EGFRm) or anaplastic lymphoma kinase translocation positive (ALK+) non-small cell lung cancer (NSCLC) is uncertain because of a lack of prospective evidence supporting tyrosine kinase inhibitor (TKI) monotherapy. Further understanding of practice heterogeneity is necessary to guide collaborative efforts in establishing guideline recommendations. We conducted an international survey among medical (MO), clinical (CO), and radiation oncologists (RO), as well as neurosurgeons (NS), of treatment recommendations for asymptomatic BrM (in non-eloquent regions) EGFRm or ALK+ NSCLC patients according to specific clinical scenarios. We grouped and compared treatment recommendations according to specialty. Responses were summarized using counts and percentages and analyzed using the Fisher exact test. A total of 449 surveys were included in the final analysis: 48 CO, 85 MO, 60 NS, and 256 RO. MO and CO were significantly more likely than RO and NS to recommend first-line TKI monotherapy, regardless of the number and/or size of asymptomatic BrM (in non-eloquent regions). Radiotherapy in addition to TKI as first-line management was preferred by all specialties for patients with ≥4 BrM. NS recommended surgical resection more often than other specialties for BrM measuring >2 cm. Recommendations for the management of BrM from EGFRm or ALK+ NSCLC vary significantly according to oncology sub-specialties. Development of multidisciplinary guidelines and further research on establishing optimal treatment strategies is warranted.


Comparison of corneal biomechanics after microincision lenticule extraction and small incision lenticule extraction.
To evaluate and compare the change in corneal biomechanical properties after microincision lenticule extraction (MILE) and small incision lenticule extraction (SMILE). In this prospective study, 60 eyes received MILE surgery with 2 mm opening incision, while 64 eyes received SMILE procedure with 5 mm opening incision. Corneal hysteresis (CH), corneal resistance factor (CRF) and 37 other biomechanical waveform parameters were quantitatively assessed using ocular response analyser (ORA) preoperatively and up to 6 months postoperatively. All changes were calculated as the difference between preoperative and postoperative values (Δ). Both CH and CRF values decreased significantly after MILE and SMILE (p<0.001). ΔCRF (o=0.028) and ΔCRF index (ΔCRF/preoperative CRF) (p=0.043) were statistically lower for all eyes at 1-week follow-up. ΔCH index (ΔCH/preoperative CH) was statistically lower at 1-week (p=0.043) and 1-month (p=0.015) follow-ups in MILE group when compared with SMILE group. In both MILE and SMILE group, ΔCH index and ΔCRF index were positively correlated with preoperative manifest refraction spherical equivalent, residual stromal thickness (RST) index (RST/preoperative central corneal thickness) and negatively correlated with lenticule thickness (p<0.05). Both MILE and SMILE procedures significantly altered the biomechanical characteristics of cornea. Smaller opening incision was associated with less reduction in ORA parameters during early postoperative period.


Noninvasive screening procedure for evaluation of bladder emptying function.
Bladder emptying function has been initially evaluated by uroflowmetry and post void residual urine measurement. Post void residual urine volume was commonly measured by a transurethral catheter which was not desirable to some patients. In the present study 7 patents with a complaint of dysuria were subjected to combined uroflowmetry and detection of post void residual urine using sector transabdominal ultrasound scanning. The volume estimation with assumption of bladder as an ellipsoid was not so accurate, nevertheless detection of post void residual urine itself was possible in all cases. Thus, the combined method appears to be very useful for evaluating bladder emptying function.


Underestimating a serving size may lead to increased food consumption when using Canada's Food Guide.
It is unclear whether Canadians accurately estimate serving sizes and the number of servings in their diet as intended by Canada's Food Guide (CFG). The objective of this study was to determine if participants can accurately quantify the size of 1 serving and the number of servings consumed per day. White, Black, South Asian, and East Asian adults (n = 145) estimated the quantity of food that constituted 1 CFG serving, and used CFG to estimate the number of servings that they consumed from their 24-h dietary recall. Participants estimated 1 serving size of vegetables and fruit (+43%) and grains (+55%) to be larger than CFG serving sizes (p ≤ 0.05); meat alternatives (-33%) and cheese (-31%) to be smaller than a CFG serving size (p ≤ 0.05); and chicken, carrots, and milk servings accurately (p > 0.05). Serving size estimates were positively correlated with the amount of food participants regularly consumed at 1 meal (p < 0.001). From their food records, all ethnicities estimated that they consumed fewer servings of vegetables and fruit (-15%), grains (-28%), and meat and alternatives (-14%) than they actually consumed, and more servings of milk and alternatives (+26%, p ≤ 0.05) than they actually consumed. Consequently, 68% of participants believed they needed to increase consumption by greater than 200 kcal to meet CFG recommendations. In conclusion, estimating serving sizes to be larger than what is defined by CFG may inadvertently lead to estimating that fewer servings were consumed and overeating if Canadians follow CFG recommendations without guidance. Thus, revision to CFG or greater public education regarding the dietary guidelines is warranted.


Perforated Meckel's diverticulum presenting with combined bowel and urinary obstruction and mimicking Crohn's disease: a case report.
Meckel's diverticulum is a common congenital anomaly of the gastrointestinal tract, but is an uncommon cause of serious complications in adults. Although cases of patients with hemorrhage, bowel obstruction or perforation associated with Meckel's diverticulum have been reported, there have been no prior reports of patients with combined urinary and bowel obstruction due to abscess formation. We describe the case of a 21-year-old man with a history of recurrent papillary thyroid cancer, but no prior abdominal surgeries, who presented with a one-month history of rectal pain and new-onset obstipation with urinary retention. He reported night sweats and weight loss, and had a second-degree relative with known Crohn's disease. A digital rectal examination was notable and revealed marked tenderness with proximal induration. A computed tomography scan of the patient's abdomen revealed a large, complex, circumferential perirectal abscess compressing the rectal lumen and base of the urinary bladder, associated with terminal ileal thickening and an ileocecal fistula. A flexible sigmoidoscopy with an endorectal ultrasound scan displayed a complex abscess with extensive mucosal and surrounding inflammation. An exploratory laparotomy revealed a Meckel's diverticulum with a large perforation at its base, positioned near the ileocecal fistula and immediately superior to the perirectal abscess. The section of small bowel containing the Meckel's diverticulum, the terminal ileum, and the cecum, were all resected, and the abscess was debrided. Pre-operative diagnosis of Meckel's diverticulum can be difficult. If the nature of the complication makes ultimate surgical management likely, an early laparoscopic or open exploration should be performed to prevent the morbidity and mortality associated with late complications.


Cytogenetic methods for detection of oxidative stress and evaluation of antioxidant therapy in hepatitis C infection.
The plasma of patients with hepatitis C contains chromosome-damaging substances, the so-called "clastogenic factors" (CFs), as this is the case for other chronic inflammatory diseases and after radiation exposure. These endogenous clastogens, formed as a consequence of increased superoxide production by inflammatory cells, can be detected with cytogenetic methods, as they are used for exogenous clastogens. The long-lived, autosustained DNA-damaging effects of CFs are risk factors for the development of cancer and leukemia. In hepatitis C, the highest clastogenic scores has been observed in patients with hepatocellular carcinoma. In agreement with the link to inflammation, clastogenic score are correlated with necro-inflammatory scores in liver biopsies. Antioxidant therapy with a powerful superoxide scavenger resulted in normalization of clastogenic scores and significant decreases in aminotransferase levels, but did not influence the virus load. Preliminary results of our study on a limited number of patients suggest that pre-treatment with antioxidants may improve the outcome of interferon/ribavirin treatment. A comparison of a three-month treatment with either interferon alone or the antioxidant alone, yielded similar results for reduction of ALT levels, but only complete normalization of clastogenic scores for the antioxidant. Further studies have to be conducted to see whether a combination of an antiviral agent with an appropriate antioxidant would allow to reduce interferon and its side effects.Combination of antioxidants with IFN/RIBA was also reported by other authors with discordant results. The CF-test can be useful in clinical trials for the choice of the appropriate antioxidant.


Machine learning for passive mental health symptom prediction: Generalization across different longitudinal mobile sensing studies.
Mobile sensing data processed using machine learning models can passively and remotely assess mental health symptoms from the context of patients' lives. Prior work has trained models using data from single longitudinal studies, collected from demographically homogeneous populations, over short time periods, using a single data collection platform or mobile application. The generalizability of model performance across studies has not been assessed. This study presents a first analysis to understand if models trained using combined longitudinal study data to predict mental health symptoms generalize across current publicly available data. We combined data from the CrossCheck (individuals living with schizophrenia) and StudentLife (university students) studies. In addition to assessing generalizability, we explored if personalizing models to align mobile sensing data, and oversampling less-represented severe symptoms, improved model performance. Leave-one-subject-out cross-validation (LOSO-CV) results were reported. Two symptoms (sleep quality and stress) had similar question-response structures across studies and were used as outcomes to explore cross-dataset prediction. Models trained with combined data were more likely to be predictive (significant improvement over predicting training data mean) than models trained with single-study data. Expected model performance improved if the distance between training and validation feature distributions decreased using combined versus single-study data. Personalization aligned each LOSO-CV participant with training data, but only improved predicting CrossCheck stress. Oversampling significantly improved severe symptom classification sensitivity and positive predictive value, but decreased model specificity. Taken together, these results show that machine learning models trained on combined longitudinal study data may generalize across heterogeneous datasets. We encourage researchers to disseminate collected de-identified mobile sensing and mental health symptom data, and further standardize data types collected across studies to enable better assessment of model generalizability.


Inhibition of chicken calpain II by proteins of the cystatin superfamily and alpha 2-macroglobulin.
Inhibition of chicken calpain II by proteins of the cystatin superfamily and alpha 2-macroglobulin was investigated. Human liver cystatins A and B, human cystatin C, chicken cystatin and rat T-kininogen were found not to be inhibitory. Inhibition was, however, observed for bovine and rat kininogens, with Ki (inhibition constant) values of 0.8 nM and 30 nM respectively. alpha 2-Macroglobulin inhibits calpain with an initial rate constant of the order of 3 X 10(4) M-1.S-1. Calpain complexed with alpha 2-macroglobulin showed only limited reactivity towards azocasein, but reacted readily with the peptide substrate Suc-Leu-Tyr-4-methyl-7-coumarylamide and with L-3-carboxy-trans-2,3-epoxypropionyl-leucylamido-(4-guanidin o)butane (E-64). The calpain in the complexes was at least partially protected from loss of activity due to autolysis. The calpain-alpha 2-macroglobulin complexes contained both the calpain subunits.


Nonspecific complement activation by streptococcal structures. I. Re-evaluation of HLA cytotoxicity inhibition.
A number of experiments have suggested that there is an antigenic relationship between the HLA complex and streptococcal bacterial structures. Using inhibition of cytotoxicity of HLA antisera as our assay system, it was demonstrated that the inhibitory effect on HLA cytotoxicity by streptococcal antigens is, in reality, due to activation and consumption of components of the alternate complement pathway. In addition, antisera prepared against streptococcal membrane antigens had no cytotoxic effect on a large panel of human lymphocytes, nor did these antisera exhibit immunofluorescent staining of lymphocytes directly. These experiments are compatible with our concept that the HLA complex may have evolved through selective evolutionary pressure as a means of escaping bacterial mimicry.


Prospective multi-center evaluation on risk factors, clinical characteristics and outcomes due to carbapenem resistance in Acinetobacter baumannii complex bacteraemia: experience from the Chinese Antimicrobial Resistance Surveillance of Nosocomial Infections (CARES) Network.
Introduction. Increasing evidence demonstrates unfavourable outcomes in bloodstream infections (BSI) due to the carbapenem-resistant Acinetobacter baumannii complex (CRAB).Aim. To investigate the differences in risk factors, clinical characteristics and outcomes in patients with A. baumannii complex BSI stratified by carbapenem resistance, a prospective multi-center study was conducted.Methodology. Information was collected in a predefined form. A total of 317 cases was included for comparison between CRAB BSI vs. carbapenem-susceptible A. baumannii complex (CSAB) BSI. Among these cases, 229 cases were defined as CRAB BSI and 88 cases as CSAB BSI.Results. Univariable analysis showed that male gender, underlying neurologic disease, prior carbapenems exposure, intensive care unit (ICU) stay, presence of central venous catheter, endotracheal intubation, tracheotomy, Foley catheter, nasogastric intubation, lower respiratory tract infections and catheter-related infections were more prevalent in CRAB BSI. Only male gender, prior carbapenems exposure and presence of endotracheal intubation persisted as independent risk factors for acquiring CRAB BSI. Patients with CRAB BSI displayed unfavourable outcomes characterized by failure of pathogen clearance, continuous fever, disease aggravation and higher incidence of 30-day all-cause mortality. Multivariate analysis demonstrated carbapenem resistance as an independent risk factor for 30-day all-cause mortality.Conclusion. Our findings reveal the epidemiological differences between CRAB BSI and CSAB BSI in a Chinese cohort. Our data suggest that carbapenem resistance has a significant impact on mortality for patients with A. baumannii complex BSI, further strengthening the importance of active prevention and control strategies for the spread of CRAB in Chinese hospitals.


Determining whether women with osteopenic bone mineral density have low, moderate, or high clinical fracture risk.
Most low-trauma fractures occur among women with osteopenic bone mineral density (BMD), a population considered to have moderate absolute fracture risk. Our purpose was to refine the fracture risk prediction in women with osteopenic BMD to determine the subgroups at lowest and highest risk. We included 2,588 women aged 50 to 90 years with osteopenic BMD (femoral neck BMD between -1 and -2.5) participating in the Canadian Multicentre Osteoporosis Study, an ongoing prospective cohort study of randomly selected Canadians. Baseline variables, in addition to known risk factors, age, and BMD, were considered for inclusion in a model for the prediction of 5-year absolute risk of low-trauma fracture. Models were derived using logistic regression and assessed by the Bayesian Information Criterion. We found an increased fracture risk among those with lower BMD (odds ratio [OR], 1.53; 95% CI, 1.06-2.21) for each decrease in femoral neck T score (eg, from -1 to -2), those with prior low-trauma fracture (OR, 2.06; 95% CI, 1.46-2.92), those with self-reported worse general health (OR, 1.35; 95% CI, 1.15-1.59) for each lower category (categories: excellent, very good, good, fair, poor), and those with height loss (OR, 1.44; 95% CI, 1.16-1.90) for each 5-cm difference between current and maximal height. The new model had yielded a better risk stratification than did a model with World Health Organization risk factors. Including risk factors such as general health and height loss can be used to provide a highly effective assessment of fracture risk among women with osteopenic BMD.


Huntington Disease: The Complexities of Making and Disclosing a Clinical Diagnosis After Premanifest Genetic Testing.
The management of patients and families affected by Huntington disease (HD) is complicated by several factors, both practical and ethical. It can be difficult to determine the onset of clinically manifest HD (mHD). In addition, it can be challenging to decide when to disclose the diagnosis to the affected individual. Firstly, the features of HD, an incurable, inherited, neurocognitive disorder that often manifests in young adulthood, influence how the person presents and accepts a diagnosis. Secondly, a positive genetic test for HD may result in a genetic diagnosis, sometimes years before the development of clinical features and the diagnosis of mHD. Thirdly, observational studies of unaffected gene expansion carriers documented HD manifestations up to 10 years before the typical presentation for diagnosis. These developments may permit earlier genetic diagnosis and information regarding the patient's likely status with respect to the development of clinical disease. Making the genetic diagnosis of HD and providing information regarding disease status, earlier rather than later, respects the person's right to know and preserves honesty in the doctor/patient relationship. Conversely, delaying the diagnosis respects the right not to know, avoids potential discrimination, and permits the person to live a "normal" life for longer, in the context of a disease without cure. This discussion has implications for other inherited and neurocognitive disorders.


[Long-term follow-up of patients with congenital heart defects].
There are about 500 new cases of congenital heart disease per year in Norway. Modern diagnostic skills, surgical techniques and follow-up programs have contributed to higher survival rates among patients. Based on international experience, 85-90 per cent of these children will survive into adulthood. Half will suffer from conditions which should be followed up by cardiologists. This article is based upon recommendations on long-term follow-up of patients with congenital heart disease.


GATA-3 transduces survival signals in osteoblasts through upregulation of bcl-x(L) gene expression.
GATA-3, a transcription factor, participates in regulating cell development, proliferation, and death. This study was aimed at evaluating the roles of GATA-3 in protecting osteoblasts against oxidative stress-induced apoptotic insults and their possible mechanisms. Pretreatment with nitric oxide (NO) for 24 hours protected osteoblasts, prepared from neonatal rat calvaria, against oxidative stress-induced apoptotic insults. Such protection involved enhancement of Bcl-X(L) messenger mRNA and protein syntheses and the translocation of this antiapoptotic protein from the cytoplasm to mitochondria. GATA-3 was detected in rat osteoblasts, and GATA-3-specific DNA-binding elements exist in the promoter region of the bcl-x(L) gene. NO preconditioning attenuated oxidative stress-caused suppression of GATA-3 mRNA and protein synthesis and the translocation of this transcription factor from the cytoplasm to nuclei. Application of GATA-3 small interfering siRNA into osteoblasts decreased the levels of this transcription factor and simultaneously inhibited Bcl-X(L) mRNA synthesis. Pretreatment with NO lowered the oxidative stress-caused alteration in the binding of GATA-3 to its specific DNA motifs. Oxidative stress-inhibited Runx2 mRNA expression, but NO preconditioning decreased such inhibition. NO pretreatment time-dependently enhanced the association of GATA-3 with Runx2. Knocking down the translation of GATA-3 using RNA interference significantly decreased the protection of NO preconditioning against oxidative stress-induced alterations of cell morphologies, DNA fragmentation, and cell apoptosis. In comparison, overexpression of GATA-3 could promote NO preconditioning-involved Bcl-X(L) expression and cell survival. Therefore, this study shows that GATA-3 plays critical roles in mediating survival signals in osteoblasts, possibly through upregulating bcl-x(L) gene expression.


Feline Femoral Fracture Fixation: What are the options?
The femur is the most commonly fractured bone in cats. Femoral fractures usually result from high-velocity trauma such as a road traffic accident or fall from a height and, as such, are associated with a wide variety of concurrent injuries. The initial focus of treatment should always be on assessment and stabilisation of the major body systems. Once any concurrent injuries have been addressed, all femoral fractures need surgical stabilisation, with the notable exception of greenstick fractures in very young cats, which can heal with cage rest alone. A number of different surgical options are available depending on the fracture type, location, equipment, surgeon experience and owner finances. Femoral fractures can vary hugely in complexity and the small size of feline bones can limit the choice of implants. Furthermore, cats can present unique challenges in the postoperative period due to their active nature and the limited means to control their exercise level. This review is aimed at general and feline-specific practitioners who have some experience of feline orthopaedics, as well as those simply wishing to expand their knowledge. The aim of this review is to help clinicians assess, plan and manage feline femoral fractures. It provides an overview of diagnostic imaging and a discussion of a range of suitable surgical options, including the principles of different types of fixation. It also highlights cat-specific issues, approaches and implants pertinent to the management of these cases. A number of original articles and textbook chapters covering many aspects of femoral fractures in cats and dogs have been published. Where possible, this review draws on information from key feline research and, where necessary, extrapolates from relevant canine literature. The authors also offer practical guidance based on their own clinical experience.


Pump/probe method for fast analysis of visible spectral signatures utilizing asynchronous optical sampling.
We report the results from a new pump/probe spectrometer for potential use in combustion diagnostics that employs asynchronous optical sampling. The instrument consists of two frequency-doubled mode-locked Nd:YAG lasers operating at slightly different repetition rates, synchronously pumping two dye lasers (rhodamine 6G) to generate the pump and probe beams. The spectral and temporal capabilities of the instrument are examined by obtaining a spectrum and an excited state decay of rhodamine B. The instrument response is shown to be proportional to pump power, probe power, and sample absorptance. Different frequency synthesizers and different modes of triggering are used to study their effect on signal stability.


Olfactory event-related potentials reflect individual differences in odor valence perception.
Investigating the neural substrates of perceived quality in olfaction using different odorants is intrinsically difficult. By utilizing individual differences in perceived quality of the odor of androstenone, we obtained a continuum of individual differences in rated valence of the same stimulus allowing investigations of its manifestation in the olfactory event-related potentials (ERPs). In an initial group consisting of 43 individuals that were screened for their verbal descriptors and sensitivity for the odor of androstenone, 22 normosmic volunteers were chosen forming 2 distinct groups with regard to verbal labels ("body odor" and "nonbody odor") for androstenone while maintaining chemical structure, concentration, and intensity constant. In the main experiment, these participants rated both intensity and pleasantness of androstenone during the recording of olfactory ERPs. There was a significant difference in rated valence between the groups but not in intensity. Participants in the body odor label group had larger amplitudes of the late positive ERP component than those in the nonbody odor label group. A negative correlation between valence and amplitudes of the late positive component for androstenone indicated that these differences were mediated by the difference in odor valence between the 2 groups. This was further supported by a comparison of ERP peaks in response to stimulation with androstenone and the invariably unpleasant hydrogen sulfide that had been used as a control. Altogether, the results suggest that the late positive component reflects the processing of odor valence. Future olfactory studies with the aim of assessing the dimension of pleasantness would benefit from the use of these interindividual differences in the perception of a specific odor.


Hue opponency: chromatic valence functions, individual differences, cortical winner-take-all opponent modeling, and the relationship between spikes and sensitivity.
Neural spike rate data are more restricted in range than related psychophysical data. For example, several studies suggest a compressive (roughly cube root) nonlinear relationship between wavelength-opponent spike rates in primate midbrain and color appearance in humans, two rather widely separated domains. This presents an opportunity to partially bridge a chasm between these two domains and to probe the putative nonlinearity with other psychophysical data. Here neural wavelength-opponent data are used to create cortical competition models for hue opponency. This effort led to creation of useful models of spiking neuron winner-take-all (WTA) competition and MAX selection. When fed with actual primate data, the spiking WTA models generate reasonable wavelength-opponent spike rate behaviors. An average psychophysical observer for red-green and blue-yellow opponency is curated from eight applicable studies in the refereed and dissertation literatures, with cancellation data roughly every 10 nm in 18 subjects for yellow-blue opponency and 15 subjects for red-green opponency. A direct mapping between spiking neurons with broadband wavelength sensitivity and human psychophysical luminance yields a power law exponent of 0.27, similar to the cube root nonlinearity. Similarly, direct mapping between the WTA model opponent spike rates and psychophysical opponent data suggests power law relationships with exponents between 0.24 and 0.41.


Synthesized femtosecond laser pulse source for two-wavelength contouring with simultaneously recorded digital holograms.
A dual-wavelength femtosecond laser pulse source and its application for digital holographic single-shot contouring are presented. The synthesized laser source combines sub-picosecond time scales with a wide reconstruction range. A center wavelength distance of the two separated pulses of only 15 nm with a high contrast was demonstrated by spectral shaping of the 50 nm broad seed spectrum centered at 800 nm. Owing to the resulting synthetic wavelength, the scan depth range without phase ambiguity is extended to the 100-microm-range. Single-shot dual-wavelength imaging is achieved by using two CMOS cameras in a Twyman-Green interferometer, which is extended by a polarization encoding sequence to separate the holograms. The principle of the method is revealed, and experimental results concerning a single axis scanner mirror operating at a resonance frequency of 0.5 kHz are presented. Within the synthetic wavelength, the phase difference information of the object was unambiguously retrieved and the 3D-shape calculated. To the best of our knowledge, this is the first time that single-shot two-wavelength contouring on a sub-ps time scale is reported.


Interpersonal forgiveness in emotion-focused couples' therapy: relating process to outcome.
The objective of this study was to relate the in-session processes involved in interpersonal forgiveness to outcome. The sample consisted of 33 couples who received 10-12 sessions of Emotion-focused couple therapy with the aim of resolving various forms of emotional injuries (i.e., transgression that violates the expectations of a close relationship, which leaves one partner feeling hurt and angry). The results of the present study were based on the analyses of 205 video-taped segments from 33 couples' therapies. Hypotheses relating the role of three in-session components of resolution, the injurer's "expression of shame"; the injured partner's "accepting response" to the shame, and the injured partner's "in-session expression of forgiveness", to outcome were tested using hierarchical linear regression analyses. Outcome measures included the Enright Forgiveness Inventory (The Enright Forgiveness Inventory user's manual. Madison: The International Forgiveness Institute, 2000), the Dyadic Adjustment Scale (Journal of Marriage and Family, 1976; 13: 723) and the The Interpersonal Trust Scale (Trust; Journal of Personality and Social Psychology, 1985; 49: 95).


External pH influences the transcriptional profile of the carbonic anhydrase, CAH-4b in Caenorhabditis elegans.
Insight into how organisms adapt to environmental stimuli has become increasingly important in recent years for identifying key virulence factors in many species. The life cycle of many pathogenic nematode species forces the organism to experience environments which would otherwise be considered stressful. One of the conditions often encountered by nematodes is a change in environmental pH. Living in a soil environment Caenorhabditis elegans will naturally encounter fluctuations in external pH. Therefore, C. elegans has the potential to provide an insight into how pathogenic nematodes survive and proliferate in these environments. We found that C. elegans can maintain over 90% survival in pH conditions ranging from pH 3 to 10. This was unrelated to the non-specific protection provided by the cuticle. Global transcriptional analysis identified many genes, which were differentially regulated by pH. The gene cah-4 encodes two putative alpha carbonic anhydrases (CAH-4a and CAH-4b), one of which was five-fold up regulated in an alkaline environment (CAH-4b). Stopped-flow analysis of CAH-4b using 35 different carbonic anhydrase inhibitors identified complex benzenesulfonamide compounds as the most potent inhibitors (K(i) 35-89nM).


Acute lymphoblastic leukemia: A population-based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980-2017.
The treatment in acute lymphoblastic Leukemia (ALL) has evolved and improved dramatically over the past four decades. We assessed the outcome of ALL overall, and the two major subsets of Philadelphia chromosome (Ph)-positive and Ph-negative ALL by age, time periods, ethnicity, median household income, and geographic county area. A total of 12 788 patients diagnosed with ALL from 1980 to 2017 were included. We performed an analysis to better evaluate the outcome evolution in ALL according to time period and patient's demographic factors. The overall 5-year survival rates have improved significantly over time, from 51% before 1990 to 72% since 2010. The survival rates for children (age 0 to 14 years) and adolescents (age 15 to 19 years) have improved from 73% and 55% before 1990 to 93% and 74% since 2010, respectively. Similarly, the rates had improved from 33% to 59% for adults 20 to 29 years old, 24% to 59% for 30 to 39 years old, and 14% to 43% for 40 to 59 years old between the two time periods. The rates remained under 30% in older patients (60+ years). Since 2010, patients with Ph-negative ALL had 5-year survival rate of 73% and those with Ph-positive ALL 50%. African Americans, Hispanic ethnicity, and lower household income were associated with inferior survival. The outcome of patients with ALL showed continued improvement across all age groups in the US. The recent introduction of targeted therapies, together with optimized supportive care, will continue to improve outcomes, particularly in older patients.


Evidence for infection, inflammation and shock in sudden infant death: parallels between a neonatal rat model of sudden death and infants who died of sudden infant death syndrome.
This study compared pathological findings from a neonatal rat model of sudden death with those from 40 sudden infant death syndrome (SIDS) infants collected at autopsy. In the rat model, influenza A virus was administered intranasally on postnatal day 10, and on day 12 a sublethal, intraperitoneal dose of Escherichia coli endotoxin; mortality was 80%. Tissue samples from the animals and infants were fixed in formaldehyde, embedded in paraffin, and sections stained with hematoxylin and eosin. Tissues from the SIDS specimens were additionally cultured for bacteria and viruses; post-mortem blood samples were evaluated for signs of inflammation. All sections were examined by a pediatric forensic pathologist familiar with SIDS pathology. Comparisons between the rat model and the human SIDS cases revealed that both exhibited gross and microscopic pathology related to organ shock, possibly associated with the presence of endotoxin. Uncompensated shock appeared to be a likely factor that caused death in both infants and rat pups. Response to a shock-inducing event might have played an important role in the events leading to death. The similarities between the neonatal rats and the human cases indicate that further research with the model might elucidate additional aspects of SIDS pathology.


Brachial Plexus Block with Liposomal Bupivacaine for Shoulder Surgery Improves Analgesia and Reduces Opioid Consumption: Results from a Multicenter, Randomized, Double-Blind, Controlled Trial.
The utility of single-injection and continuous peripheral nerve blocks is limited by short duration of analgesia and catheter-related complications, respectively. This double-blind, multicenter trial evaluated the efficacy, safety, and pharmacokinetics of single-injection, ultrasound-guided brachial plexus block (BPB) with liposomal bupivacaine (LB) added to a standardized pain management protocol for shoulder surgery. Adults undergoing total shoulder arthroplasty or rotator cuff repair were randomized to receive LB 133 mg, LB 266 mg (pharmacokinetic and safety analyses only), or placebo, added to a standardized analgesia protocol. The primary end point was area under the curve (AUC) of visual analog scale pain intensity scores through 48 hours postsurgery. Secondary end points were total opioid consumption, percentage of opioid-free patients, and time to first opioid rescue through 48 hours. Pharmacokinetic samples were collected through 120 hours and on days 7 and 10. Adverse events were documented. One hundred fifty-five patients received treatment (LB 133 mg, N = 69; LB 266 mg, N = 15; placebo, N = 71). BPB with LB 133 mg was associated with significantly improved AUC of pain scores (least squares mean [SE] = 136.4 [12.09] vs 254.1 [11.77], P < 0.0001), opioid consumption (least squares mean [SE] = 12.0 [2.27] vs 54.3 [10.05] mg, P < 0.0001), median time to opioid rescue (4.2 vs 0.6 h, P < 0.0001), and percentage of opioid-free patients (treatment difference = 0.166, 95% confidence interval = 0.032-0.200, P = 0.008) through 48 hours vs placebo. Adverse event incidence was comparable between groups. Single-injection BPB with LB 133 mg provided analgesia through 48 hours postsurgery with reduced opioid use compared with placebo after shoulder surgery.


GSK3beta in ethanol neurotoxicity.
Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation in North America ahead of Down syndrome and cerebral palsy. Ethanol exposure during development causes multiple abnormalities in the brain such as permanent loss of neurons, ectopic neurons, and alterations in synaptogenesis and myelinogenesis. These alcohol-induced structural alterations in the developing brain underlie many of the behavioral deficits observed in FASD. The cellular and molecular mechanisms of ethanol neurotoxicity, however, remain unclear. Ethanol elicits cellular stresses, including oxidative stress and endoplasmic reticulum stress. Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase, responds to various cellular stresses. GSK3beta is particularly abundant in the developing CNS, and regulates diverse developmental events in the immature brain, such as neurogenesis and neuronal differentiation, migration, and survival. Available evidence indicates that the activity of GSK3beta in the CNS is affected by ethanol. GSK3beta inhibition provides protection against ethanol neurotoxicity, whereas high GSK3beta activity/expression sensitizes neuronal cells to ethanol-induced damages. It appears that GSK3beta is a converging signaling point that mediates some of ethanol's neurotoxic effects.


Featured Article: Bidirectional Effects of Sleep and Sedentary Behavior Among Toddlers: A Dynamic Multilevel Modeling Approach.
To examine the bidirectional effects of objectively measured nighttime sleep and sedentary activity among toddlers. Actical accelerometer data were analyzed for 195 toddlers participating in an obesity prevention trial (mean age = 27 months). Toddlers wore the accelerometers for up to 7 consecutive days. Nighttime sleep was defined as the number of minutes asleep between the hours of 8 pm and 8 am the following morning. Sedentary behavior (in minutes) was defined using previously established Actical cut points for toddlers. Variables were lagged and parsed into latent within- and between-person components, using dynamic structural equation modeling (DSEM). Toddlers spent an average of 172 min (∼3 hr) in sedentary activity and slept an average of 460 min (∼8 hr) per night. An autoregressive cross-lagged multilevel model revealed significant autoregression for both sleep and sedentary activity. Cross-lagged values revealed that decreased sleep predicted increased next-day sedentary activity, and sedentary activity predicted that night's sleep. For 89% of the sample, the within-person standardized cross-lagged effects of sleep on sedentary were larger than the cross-lagged effects of sedentary on sleep. Results suggest that, on average, nighttime sleep is a stronger predictor of subsequent sedentary behavior (compared with the reverse), and this is the case for the majority of toddlers. Findings highlight the importance of interindividual associations between sleep and sedentary activity. The present study is an example of how DSEM methods can be used to ask questions about Granger-causal cross-lagged relations between variables, both within and between individuals.


Intrathecal anesthesia and recovery from radical prostatectomy: a prospective, randomized, controlled trial.
Previous studies suggest that intraoperative anesthetic care may influence postoperative pain and recovery from surgery. The authors tested the hypothesis that the addition of intrathecal analgesia to general anesthesia would improve long-term functional status and decrease pain in patients undergoing radical retropubic prostatectomy. One hundred patients received either general anesthesia supplemented with intravenous fentanyl or general anesthesia preceded by intrathecal administration of bupivacaine (15 mg), clonidine (75 microg), and morphine (0.2 mg). Patients and providers were masked to treatment assignment. All patients received multimodal pain management postoperatively. Primary outcomes included pain and functional status over the first 12 postoperative weeks. Patients receiving intrathecal analgesia required more intravenous fluids and vasopressors intraoperatively. Pain was well controlled throughout the study (mean numerical pain scores < 3 in both groups at all times studied). Intrathecal analgesia decreased pain and supplemental intravenous morphine use over the first postoperative day but increased the frequency of pruritus. Pain and functional status after discharge from the hospital did not differ between groups. Intrathecal analgesia significantly decreased the duration of hospital stay (from 2.8 +/- 2.0 to 2.1 +/- 0.5 days; P < 0.01) as a result of five patients in the control group who stayed in the hospital more than 3 days. The benefits of improved immediate analgesia and decreased morphine requirements resulting from intrathecal analgesia must be weighed against factors such as pruritus, increased intraoperative requirement for fluids and vasopressors, and resources needed to implement this modality. Further studies are needed to determine the significance of the decrease in duration of hospital stay.


Class II antigen (HLA-DR) expression by intestinal epithelial cells in inflammatory diseases of colon.
Eighty four colonic biopsy specimens were obtained from patients with ulcerative colitis, Crohn's disease, radiation colitis, infectious colitis, and from normal controls. Paired specimens were examined by histological and immunohistochemical methods using monoclonal antibodies to the beta chain of HLA-DR antigen. The expression of HLA-DR antigen in mucosal epithelial cells was strongly related to whether the specimens were actively inflamed: epithelial cells from 34 of 37 inflamed specimens (nu three of 42 non-inflamed specimens) were HLA-DR positive (p less than 0.0001). Epithelial cells were uniformly HLA-DR negative in specimens from normal control patients despite the presence of HLA-DR positive lymphoid cells and macrophages in the lamina propria. Epithelial cells in specimens from patients with ulcerative colitis, Crohn's disease, and radiation colitis were HLA-DR positive in 30 of 33 inflamed biopsy specimens and in only three of 25 non-inflamed specimens (p less than 0.0001). Epithelial cells were HLA-DR positive in nine of 10 biopsy specimens from patients with acute infectious colitis (p less than 0.01).


Taming of fluoroform: direct nucleophilic trifluoromethylation of Si, B, S, and C centers.
Fluoroform (CF(3)H), a large-volume by-product of the manufacture of Teflon, refrigerants, polyvinylidene fluoride (PVDF), fire-extinguishing agents, and foams, is a potent and stable greenhouse gas that has found little practical use despite the growing importance of trifluoromethyl (CF3) functionality in more structurally elaborate pharmaceuticals, agrochemicals, and materials. Direct nucleophilic trifluoromethylation using CF(3)H has been a challenge. Here, we report on a direct trifluoromethylation protocol using close to stoichiometric amounts of CF(3)H in common organic solvents such as tetrahydrofuran (THF), diethyl ether, and toluene. The methodology is widely applicable to a variety of silicon, boron, and sulfur-based electrophiles, as well as carbon-based electrophiles.


An assessment of the efficacy of blue light phototherapy in the treatment of acne vulgaris.
Acne vulgaris is a common skin condition that affects 8 out of 10 people. It varies from mild to severe, and different treatments target various aspects of the disease. Propionibacterium acnes, one of the culprits involved in the pathogenesis of acne vulgaris, is the main target of all major medical treatments used. Studies conducted in recent years have shown favorable effects within the visible light spectrum for the treatment of acne vulgaris. In this study, we have evaluated the use of intense blue light within the spectral range of 415-425 nm (peak 420 nm) in the treatment of acne vulgaris. Twenty-one patients with mild to moderate facial acne were treated with blue light phototherapy. All patients were given 14-min treatment sessions twice a week for 4 weeks. Acne severity was assessed using the Leeds Technique for grading and lesion counts. Disability was assessed using the Dermatology Life Quality Index (DLQI). In addition, standard digital and cross-polarized light photographs were taken and graded by a blinded evaluator. Visual analog scale (VAS) scores and cultures for P. acnes were carried out before starting the treatment and upon completion of the treatment. Significant improvement was achieved in the Leeds Acne Grade (P = 0.001). The inflammatory (P = 0.001) and noninflammatory (P = 0.06) lesion counts also improved significantly. A similar change was noted in the DLQI (P = 0.001); a degree of significance was also achieved in the patients' and the investigators' VAS scores (P = 0.01 and P = 0.001, respectively). P. acnes colony counts failed to show a significant decrease at the end of the treatment and remained almost constant (P = 0.660). We believe that blue light does appear to have some role in the management of acne and may be beneficial for the treatment of a select group of mild to moderate acne patients.


[The effect of glial cells in the function and development of the nervous system in Caenorhabditis elegans].
There are three types of glial cells in Caenorhabditis elegans (C. elegans for short): sheath glia, socket glia and glutamate receptor glia. They are mainly located in four sensory organs including the amphid, the cephalic organ, the outer labial sensilla and the inner labial sensilla. C. elegans glial cells play key roles in dendrite extension, neurite guidance and extension, and are essential for synaptogenesis and maintain the normal morphology and the function of sensory nerve endings as well. A recent study shown that some nematode neurons are derived from the glial cells. Moreover, nematodes glial cells can directly modulate the function of sensory neurons. Some glial cells can also respond to certain external stimuli, such as mechanical stimulation, and adjust the accompanying neuronal activities.The article summarizes the progress on effects of nematodes glial cells on the nervous system development and function.


Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension.
Primary pulmonary hypertension is a rare disease of childhood, which carries a poor prognosis. Patients often present with severe exercise limitation, and untreated life expectancy is less than 1 year. Pharmacological intervention is directed towards reduction of the raised pulmonary artery pressure with vasodilator treatment, initially with calcium antagonists, although more recently long term prostacyclin treatment has shown benefit in some patients. Heart-lung transplantation remains an option for children with severe disease refractory to therapeutic treatment. A 4 year old Bangladeshi girl with dyspnoea, cyanosis, and signs of a low cardiac output, is described. Initial treatment with prostacyclin was gradually reduced, and maintenance treatment with oral sildenafil (Viagra; Pfizer) instituted. At follow up 3 months later, her exercise capacity was greatly improved and she continues to enjoy a good quality of life without obvious side effects. In view of the encouraging initial results, this may become an acceptable adjunct in treating this patient group.


The bone marrow is the primary site of thrombopoiesis.
Megakaryocytes generate thousands of platelets over their lifespan. More recently, roles in infection and inflammation have been reported. These findings have driven a study of extra-medullary thrombopoiesis, and megakaryocytes have been increasingly reported within the spleen and lung. However, the relative abundance of megakaryocytes in these organs compared to the bone marrow and the scale of their contribution to the platelet pool in steady state remains controversial. We investigated the relative abundance of megakaryocytes in the adult murine bone marrow, spleen, and lung using whole-mount light sheet and quantitative histological imaging, flow cytometry, intravital imaging, and an assessment of scRNA-seq repositories. Flow cytometry revealed significantly higher numbers of hematopoietic stem and progenitor cells and megakaryocytes in the murine bone marrow compared to spleens or perfused lungs. Two-photon intravital and light-sheet microscopy, as well as cryosections confirmed these findings. Moreover, ex-vivo cultured megakaryocytes from the bone marrow subject to static or microfluidic platelet production assays had a higher capacity for proplatelet-formation than MKs from other organs. Analysis of previously published murine and human scRNA-seq datasets revealed that only a marginal fraction of megakaryocyte-like cells can be found within the lung and most likely only marginally contribute to platelet production in the steady state.


ThioredoxinA1 Controls the Oxidative Stress Response of Francisella tularensis Live Vaccine Strain (LVS).
Francisella tularensis is an intracellular, Gram-negative bacterium known for causing a disease known as tularemia in the Northern Hemisphere. F. tularensis is classified as a category A select agent by the CDC based on its possible use as a bioterror agent. F. tularensis overcomes oxidative stress encountered during its growth in the environment or host macrophages by encoding antioxidant enzymes such as superoxide dismutases, catalase, and alkylhydroperoxy reductase. These antioxidant enzymes are regulated by the oxidative stress response regulator, OxyR. In addition to these antioxidant enzymes, F. tularensis also encodes two thioredoxins, TrxA1 (FTL_0611) and TrxA2 (FTL_1224); however, their role in the oxidative stress response of F. tularensis is not known. This study investigated the role of thioredoxins of F. tularensis in the oxidative stress response and intracellular survival. Our results demonstrate that TrxA1 but not TrxA2 plays a major role in the oxidative stress response of F. tularensis. Most importantly, this study elucidates a novel mechanism through which the TrxA1 of F. tularensis controls the oxidative stress response by regulating the expression of the master regulator, oxyR. Further, TrxA1 is required for the intramacrophage survival and growth of Francisella. Overall, this study describes a novel role of thioredoxin, TrxA1, in regulating the oxidative stress response of F. tularensis. IMPORTANCE The role of thioredoxins in the oxidative stress response of F. tularensis is not known. This study demonstrates that of the two thioredoxins, TrxA1 is vital to counter the oxidative stress in F. tularensis live vaccine strain (LVS). Furthermore, this study shows differences in the well-studied thioredoxins of Escherichia coli. First, the expression of TrxA1 of F. tularensis is independent of the oxidative stress response regulator, OxyR. Second and most importantly, TrxA1 regulates the expression of oxyR and, therefore, the OxyR-dependent oxidative stress response of F. tularensis. Overall, this study reports a novel regulatory role of TrxA1 of F. tularensis in the oxidative stress response.


Tuberculosis prophylaxis with levofloxacin in liver transplant patients is associated with a high incidence of tenosynovitis: safety analysis of a multicenter randomized trial.
It is necessary to develop a safe alternative to isoniazid for tuberculosis prophylaxis in liver transplant recipients. This study was designed to investigate the efficacy and safety of levofloxacin. An open-label, prospective, multicenter, randomized study was conducted to compare the efficacy and safety of levofloxacin (500 mg q24h for 9 months) initiated in patients awaiting liver transplantation and isoniazid (300 mg q24h for 9 months) initiated post-transplant when liver function was stabilized. Efficacy was measured by tuberculosis incidence at 18 months after transplantation. All adverse events related to the medication were recorded. CONSORT guidelines were followed in order to present the results. The safety committee suspended the study through a safety analysis when 64 patients had been included (31 in the isoniazid arm and 33 in the levofloxacin arm). The reason for suspension was an unexpected incidence of severe tenosynovitis in the levofloxacin arm (18.2%). Although the clinical course was favorable in all cases, tenosynovitis persisted for 7 weeks in some patients. No patients treated with isoniazid, developed tenosynovitis. Only 32.2% of patients randomized to isoniazid (10/31) and 54.5% of patients randomized to levofloxacin (18/33, P = .094) completed prophylaxis. No patient developed tuberculosis during the study follow-up (median 270 days). Levofloxacin prophylaxis of tuberculosis in liver transplant candidates is associated with a high incidence of tenosynovitis that limits its potential utility.


Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability.
CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types.


Cefotaxime therapy. Evaluation of its effect on bacterial meningitis, CSF drug levels, and bactericidal activity.
Cefotaxime sodium was evaluated in the treatment of ten patients with bacterial meningitis. Seven of the patients were infected with unusual and difficult to eradicate pathogens. Eight of the ten patients had a favorable clinical response and rapid sterilization of their CSF. Trough CSF levels of cefotaxime (range, 5.6 to 44.3 micrograms/mL) and desacetylcefotaxime (3.7 to 44.0 micrograms/mL) were manyfold greater than the minimal bactericidal concentrations of the causative pathogens with the exception of the one Pseudomonas aeruginosa isolate. Trough CSF bactericidal titers ranged from 1:16 to 1:4,096 or more (median, 1:256) in the nine patients with susceptible pathogens. Trough cefotaxime and desacetylcefotaxime levels and bactericidal titers were maintained or actually increased over the course of therapy. Cefotaxime appears to be a promising new agent for the treatment of bacterial meningitis.


Microsatellite instability is often observed in esophageal carcinoma patients with allelic loss in the FHIT/FRA3B locus.
We have previously reported a significant correlation between the progression of colorectal carcinoma and the loss of Fhit and Msh2 expression. This observation led us to investigate the effect of an allelic loss of the FHIT gene on esophageal cancer when coupled with a deficient mismatch repair system. In this study, 8 of 42 patients with esophageal cancer had microsatellite instability (MSI), and 29 cases demonstrated allelic loss (loss of heterozygosity or homozygous deletion) at the FHIT/FRA3B locus. All 8 MSI-positive cases showed allelic loss, while 13 of 34 MSI-negative cases retained both alleles, and a significant correlation was found between the incidence of MSI and allelic loss (p < 0.05). On the other hand, only 1 of the 8 MSI-positive patients exhibited neither Msh2 nor Fhit protein expression in both normal and carcinoma epithelial tissues, but neither a relationship between Msh2 expression and Fhit expression nor with the incidence of MSI was noted. This result indicated that the disruption of the mismatch repair system of Msh2 does not mainly lead to allelic loss of the FHIT/FRA3B locus as well as MSI in esophageal cancer. We concluded that MSI is significantly related to the allelic loss in the FHIT/FRA3B region, but Msh2 might be unrelated to the progression or oncogenic process in esophageal cancer.


The Impact of Different Exercise Intensities on Vasodilation and Shear Rate Patterns in Children.
The effect of exercise intensity on vasodilator function is poorly understood in children. The authors compared the acute effect of high-intensity interval exercise (HIIE) with moderate-intensity steady-state exercise (MISS) on postexercise vasodilation and shear patterns in 7- to 12- year-old children. Superficial femoral artery diameter, shear rates, and flow-mediated dilation were measured pre, immediately following (post), and 1 hour after (post60) HIIE (six 1-min sprints at 90% peak power [Wmax], with 1-min recovery) and MISS (15 min at 44% Wmax). Baseline superficial femoral artery diameter increased similarly following both HIIE (pre 4.23 [0.41] mm, post 4.73 [0.56] mm) and MISS (pre 4.28 [0.56] mm, post 4.59 [0.64] mm), returning to preexercise values post60. Blood flow and antegrade shear rate were increased post HIIE and MISS, but to a greater extent, post HIIE (P < .05). Retrograde shear rate was attenuated post both exercise conditions and remained post60 (P < .001). There was a decline in flow-mediated dilation postexercise (HIIE Δ -2.9%; MISS Δ -2.4%), which was no longer apparent when corrected for baseline diameter. Acute bouts of external work-matched HIIE or MISS exert a similar impact on shear-mediated conduit artery vasodilation and flow-mediated dilation in children, and this is reversed 1 hour after exercise.


Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.
Valproate is an anticonvulsant drug with strong preclinical evidence for reducing anxiety behaviour in rodents but no clear clinical evidence. To motivate clinical trials, we here investigate the use of valproate in a translational human model of anxiety behaviour. In a double-blind, randomised, placebo-controlled trial, n = 118 healthy participants played a previously validated approach/avoidance conflict computer game to measure anxiety-like behaviour, while under 400 mg valproate, under 200 mg of the established anxiolytic/anticonvulsant pregabalin, or under placebo. Saccadic peak velocity and subjective ratings were assessed to control for drug-induced sedation. Compared to placebo, valproate and pregabaline were anxiolytic in the primary outcome, and several secondary outcomes. Bayesian model comparison decisively demonstrated no differences between the two drugs. Subjective and objective sedation was significantly more pronounced under pregabalin than valproate, but did not explain anxiolytic effects. We demonstrate acute anxiolytic properties of valproate in healthy humans. Both drugs have similar anxiolytic properties at the doses used. Valproate is less sedative than pregabalin. Our results suggest clinical trials on the use of valproate in anxiolytic treatment. More generally, we propose a strategy of screening drugs in human preclinical models that can directly be compared across species, such as the approach/avoidance conflict computer game used here. This approach could thus facilitate translational anxiety research.


Strongly Coupled Ag/Sn-SnO2 Nanosheets Toward CO2 Electroreduction to Pure HCOOH Solutions at Ampere-Level Current.
Electrocatalytic reduction of CO2 converts intermittent renewable electricity into value-added liquid products with an enticing prospect, but its practical application is hampered due to the lack of high-performance electrocatalysts. Herein, we elaborately design and develop strongly coupled nanosheets composed of Ag nanoparticles and Sn-SnO2 grains, designated as Ag/Sn-SnO2 nanosheets (NSs), which possess optimized electronic structure, high electrical conductivity, and more accessible sites. As a result, such a catalyst exhibits unprecedented catalytic performance toward CO2-to-formate conversion with near-unity faradaic efficiency (≥ 90%), ultrahigh partial current density (2,000 mA cm-2), and superior long-term stability (200 mA cm-2, 200 h), surpassing the reported catalysts of CO2 electroreduction to formate. Additionally, in situ attenuated total reflection-infrared spectra combined with theoretical calculations revealed that electron-enriched Sn sites on Ag/Sn-SnO2 NSs not only promote the formation of *OCHO and alleviate the energy barriers of *OCHO to *HCOOH, but also impede the desorption of H*. Notably, the Ag/Sn-SnO2 NSs as the cathode in a membrane electrode assembly with porous solid electrolyte layer reactor can continuously produce ~ 0.12 M pure HCOOH solution at 100 mA cm-2 over 200 h. This work may inspire further development of advanced electrocatalysts and innovative device systems for promoting practical application of producing liquid fuels from CO2.


[Can ultrasonography replace arteriography in arteriosclerosis of the lower limb?].
Arteriography is the imaging modality of choice before lower limb revascularization, because it allows pinpointing of the diseased arteries and planning of the treatment strategy, be it PTA or bypass grafting. However, a 2-3% risk of complications, makes assessment of non-invasive alternatives mandatory. Insufficient contrast filling of infrapopliteal arteries distal to severe lesions have also challenged the status of arteriography as the gold standard before revascularisation. The use of duplex arterial mapping is a promising alternative, as it has the highest agreement in the femoral segment and the lowest in the infra-popliteal segment. Duplex arterial mapping is a reliable means of predicting whether patients will require a bypass graft or an endovascular procedure, and, if surgery is required, in predicting the actual location of both anastomoses.


Measuring Value in Spine Care Using the PROMIS-Preference Scoring System.
A transition to value-based care requires a thorough understanding of the costs and impacts of various interventions on patients' overall health utility. The Patient-Reported Outcomes Measurement Information System (PROMIS) has gained popularity and is frequently used to assess physical, mental, and social health domains in clinical and research settings. To assess health utility, the PROMIS-Preference (PROPr) score, a societal preference-based measure, has been proposed to produce a single estimate of health utility. We determined the psychometric properties (validity and responsiveness) of the PROPr score as a health state utility measure in patients undergoing spine surgery. We hypothesized that PROPr score would be lower in the presence of comorbid conditions and lower socioeconomic status and in those with more severe pain-related disability and would be responsive to changes in health status following spine surgery. In this prospective cohort study, 904 adults presented for cervical (n = 359) and/or lumbar (n = 622) conditions, and 624 underwent surgery, from August 2019 through January 2022. To assess concurrent validity, we correlated the PROPr score with Neck Disability Index (NDI)/Oswestry Disability Index (ODI) values. To assess known-groups validity, we regressed the PROPr score on participant age, sex, pain-related disability, and social determinants of health. To assess responsiveness, we used an anchor-based approach, evaluating change from preoperatively to 6 and 12 months postoperatively anchored by the Patient Global Impression of Change. A p level of <0.05 was considered significant. The median overall preoperative PROPr score was 0.20 (interquartile range [IQR], 0.10 to 0.32; range, -0.02 to 0.95). The PROPr score was associated with higher educational attainment (p = 0.01), higher household income (p < 0.001), and a greater number of comorbid conditions (p = 0.04). The median PROPr score decreased (worse health utility) with greater disability (NDI, 0.44 [none] to 0.09 [severe/complete], p < 0.001; ODI, 0.57 [none] to 0.08 [severe/complete], p < 0.001). The change in the median PROPr score differed in participants who rated their postoperative health as improved (0.17) compared with little or no change (0.04; p < 0.001) or worse (-0.06; p = 0.025) at 6 months and in those who rated their health as improved (0.15) compared with little or no change (0.02; p < 0.001) or worse (-0.05; p = 0.043) at 12 months. The PROPr score is a valid and responsive preference-based assessment of health utility for patients undergoing spine surgery. It can be calculated from PROMIS outcome data. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Building consensus on key priorities for rural health care in South Africa using the Delphi technique.
South Africa is currently undergoing major health system restructuring in an attempt to improve health outcomes and reduce inequities in access. Such inequities exist between private and public health care and within the public health system itself. Experience shows that rural health care can be disadvantaged in policy formulation despite good intentions. The objective of this study was to identify the major challenges and priority interventions for rural health care provision in South Africa thereby contributing to pro-rural health policy dialogue. The Delphi technique was used to develop consensus on a list of statements that was generated through interviews and literature review. A panel of rural health practitioners and other stakeholders was asked to indicate their level of agreement with these statements and to rank the top challenges in and interventions required for rural health care. Response rates ranged from 83% in the first round (n=44) to 64% in the final round (n=34). The top five priorities were aligned to three of the WHO health system building blocks: human resources for health (HRH), governance, and finance. Specifically, the panel identified a need to focus on recruitment and support of rural health professionals, the employment of managers with sufficient and appropriate skills, a rural-friendly national HRH plan, and equitable funding formulae. Specific policies and strategies are required to address the greatest rural health care challenges and to ensure improved access to quality health care in rural South Africa. In addition, a change in organisational climate and a concerted effort to make a career in rural health appealing to health care workers and adequate funding for rural health care provision are essential.


Validation of quantitative digital subtraction radiography using the electronically guided alignment device/impression technique.
The electronically guided alignment device (EGAD) has been demonstrated to function well with a custom fabricated stent for taking radiographs for subtraction. The objective of this study is to demonstrate that this device functions well when used with an impression bite-block rather than a full arch acrylic stent. Nineteen subjects participated. Two vinyl siloxane impressions were made for each subject and a pair of x-rays was taken with each impression. The location for study was divided among 7 for the maxillary premolar-1st molar region, 6 for the mandibular premolar-1st molar region, and 6 for the incisor-canine region. To simulate bone change 3 bone chips (approximately 1, 7, and 10 mg) were positioned in the mucobuccal fold when one of each pair of x-rays was taken. Pairs of radiographs were subtracted and the bone change (chips) isolated by thresholding to determine their area. An aluminum ramp was used to determine volume. A strong linear relationship between actual chip weight and equivalent aluminum volume (r2 = 0.64, P < 0.001) was obtained for all regions of the mouth when considered together. The strongest relationship of the 3 regions was for mandibular premolar-1st molar sites, r2 = 0.78. These data indicate that the EGAD/impression technique is suitable for taking radiographs in all areas of the mouth for quantitative digital subtraction.


Morphology and Molecular Phylogeny of a New Marine, Sand-dwelling Dinoflagellate Genus, Pachena (Dinophyceae), with Descriptions of Three New Species.
Marine benthic dinoflagellates are interesting not only because some epiphytic genera can cause harmful algal blooms but also for understanding dinoflagellate evolution and diversification. Our understanding of their biodiversity is far from complete, and many thecate genera have unusual tabulation patterns that are difficult to relate to the diverse known phytoplankton taxa. A new sand-dwelling genus, Pachena gen. nov., is described based on morphological and DNA sequence data. Three species were discovered in distant locations and are circumscribed, namely, P. leibnizii sp. nov. from Canada, P. abriliae sp. nov. from Spain, and P. meriddae sp. nov. from Italy. All species are tiny (about 9-23 μm long) and heterotrophic. Species are characterized by their tabulation (APC 4' 3a 6'' 5c 5s 5''' 2''''), an apical hook covering the apical pore, an ascending cingulum, and a sulcus with central list. The first anterior intercalary plate is uniquely "sandwiched" between two plates. The species share these features and differ in the relative sizes and arrangements of their plates, especially on the epitheca. The ornamentation of thecal plates is species-specific. The new molecular phylogenies based on SSU and LSU rDNA sequences contribute to understanding the evolution of the planktonic relatives of Pachena, the Thoracosphaeraceae.


Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat-shock protein 70.
Toll-like receptor 4 (TLR4) is involved in ozone (O3)-induced pulmonary hyperpermeability and inflammation, although the downstream signaling events are unknown. The aims of our study were to determine the mechanism through which TLR4 modulates O3-induced pulmonary responses and to use transcriptomics to determine potential TLR4 effector molecules. C3H/HeJ (HeJ; Tlr4 mutant) and C3H/HeOuJ (OuJ; Tlr4 normal) mice were exposed continuously to 0.3 ppm O3 or filtered air for 6, 24, 48, or 72 hr. We assessed inflammation using bronchoalveolar lavage and molecular analysis by mRNA microarray, quantitative RT-PCR (real-time polymerase chain reaction), immunoblots, immunostaining, and ELISAs (enzyme-linked immunosorbent assays). B6-Hspa1a/Hspa1btm1Dix/NIEHS (Hsp70-/-) and C57BL/6 (B6; Hsp70+/+ wild-type control) mice were used for candidate gene validation studies. O3-induced TLR4 signaling occurred through myeloid differentiation protein 88 (MyD88)-dependent and -independent pathways in OuJ mice and involved multiple downstream pathways. Genomewide transcript analyses of lungs from air- and O3-exposed HeJ and OuJ mice identified a cluster of genes that were significantly up-regulated in O3-exposed OuJ mice compared with O3-exposed HeJ mice or air-exposed controls of both strains; this cluster included genes for heat-shock proteins (e.g., Hspa1b, Hsp70). Moreover, O3-induced inflammation, MyD88 up-regulation, extracellular-signal-related kinase-1/2 (ERK1/2) and activator protein-1 (AP-1) activation, and kerotinocyte-derived chemokine (KC) protein content were significantly reduced in Hspa1a/Hspa1btm1Dix (Hsp70-/-) compared with Hsp70+/+ mice (p < 0.05). These studies suggest that HSP70 is an effector molecule downstream of TLR4 and is involved in the regulation of O3-induced lung inflammation by triggering similar pathways to TLR4. These novel findings may have therapeutic and preventive implications for inflammatory diseases resulting from environmental exposures.


Arabidopsis CAMTA family proteins enhance V-PPase expression in pollen.
The pollen-specific cis-acting region of the AVP1 gene is involved in the expression of the Arabidopsis V-PPase gene during pollen development. We isolate AtCAMTA5, which binds to the 38-bp pollen-specific cis-acting region, by one-hybrid screening using the cis-acting region as a probe. The green fluorescent protein-fused AtCAMTA5 is specifically localized to the nucleus in Arabidopsis suspension cultured cells. The promoter-beta-glucuronidase reporter experiment shows the expression not only of AtCAMTA5 but also of AtCAMTA1 in pollen. In particular, AtCAMTA1 is specifically expressed in pollen. Both the one-hybrid analysis in the reporter yeast and in vivo transient effector-reporter analysis in Arabidopsis suspension cultured cells revealed that AtCAMTA1 could regulate gene expression depending on the CGCG-box within the 38-bp pollen-specific cis-acting region. These results indicate that AtCAMTA1 as well as AtCAMTA5 possibly enhance AVP1 expression in pollen.


Beta 1- and beta 2-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart.
The augmentation of cardiac inotropism induced by electrical stimulation of acutely decentralized efferent preganglionic sympathetic axons is reduced after the administration of timolol into the major ipsilateral intrathoracic ganglia. Thus it has been proposed that, in addition to nicotinic synapses, beta-adrenergic ones exist in intrathoracic ganglia that are involved in the efferent sympathetic regulation of the mammalian heart. Whether these are beta 1- as opposed to beta 2-adrenoceptor subtypes is unknown. In the present series of experiments, acutely decentralized canine efferent preganglionic sympathetic axons were stimulated before and after the administration of beta 1 (atenolol)- or beta 2 (ICI 118551)-selective adrenoceptor antagonists into the ipsilateral stellate and middle cervical ganglia to determine whether beta 1- or beta 2-adrenoceptors exist in intrathoracic ganglia that are involved in cardiac regulation. Augmentations of right and left ventricular inotropism induced by efferent preganglionic sympathetic axon stimulation were attenuated when either agent was administered into the major ipsilateral intrathoracic sympathetic ganglia. Myocardial liberation of norepinephrine evoked by these stimulations was also reduced after intraganglionic administration of either agent. These data indicate that canine intrathoracic neurons contain beta 1- and beta 2-adrenoceptors that are involved in the efferent sympathetic regulation of the heart.


Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar.
A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% for Candida albicans versus 69.8% for the other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild-type (non-WT) strains (strains for which MICs were above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) among strains of C. albicans and C. orthopsilosis contained FKS hot spot mutations, including heterozygous mutations in FKS1 For C. tropicalis, the Etest appeared to overestimate strains non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains, respectively, had values above the epidemiological cutoff value. However, no FKS mutations were identified in this species. For all other species, micafungin best reported the echinocandin non-WT strains relative to the FKS genotype, as anidulafungin tended to overestimate non-wild-type strains. Besides C. tropicalis, few strains were classified as non-WT for amphotericin B.


[Adhesion and aggregation in the subendothelium: hereditary platelet function disorder].
Platelet adhesion to a thrombogenic surface and adhesion-induced aggregation were investigated using a perfusion system at a blood flow rate similar to that observed in arteries. Morphometric measurements revealed diminished adhesion of platelets but normal surface-induced aggregation with blood of patients with von Willebrand's disease and with Bernard-Soulier syndrome. In contrast, surface-induced aggregation was defective with blood of patients with storage pool disease, thrombasthenia and with blood of healthy volunteers after Aspirin ingestion. These findings may explain the defective hemostasis in these patients. They suggest that platelet adhesion and aggregation are governed by different mechanisms.


The toxic mind: the biology of mental illness and violence.
The continual suppression of emotions during fight or flight reactions results in atrophy and endogenous toxicosis in noradrenergic neurons. Toxic metabolites interfere with neurotransmission, causing depression. During periodic detoxification crises, excess norepinephrine floods synapses overexcite postsynaptic neurons, and cause symptoms ranging from mild anxiety to violent behavior. When toxic metabolites, which may include excess dopamine, epinephrine, serotonin, gamma-aminobutyric acid, peptides, amino acids, and various metabolic waste products, are bound to noradrenergic receptor sites, these sites become unavailable to norepinephrine. Excitation of postsynaptic neurons is diminished and depression returns. The diverse proteins in receptor sites presumed to be specific for false neurotransmitters may instead encode specific memories. The shift in depressive and excitatory behavior is characteristic of most psychiatric disorders, addictions, Alzheimer's disease, Parkinson's disease, and psychosomatic disorders. Recovery is a detoxification process and can be facilitated by therapy that involves re-experiencing childhood traumas, releasing, and redirecting repressed emotions.


Associations of methadone and buprenorphine-naloxone doses with unregulated opioid use, treatment retention, and adverse events in prescription-type opioid use disorders: Exploratory analyses of the OPTIMA study.
Buprenorphine/naloxone (BUP-NX) and methadone are used to treat opioid use disorder (OUD), yet there is insufficient evidence on the impact of doses on interventions' effectiveness and safety when treating OUD attributable to other opioids than heroin. We explored associations between methadone and BUP-NX doses and treatment outcomes using data from OPTIMA, a 24-week, pragmatic, open-label, multicenter, pan-Canadian, randomized controlled, two-arm parallel trial with participants (N = 272) with OUD who primarily use opioids other than heroin. Participants were randomized to receive flexible take-home BUP-NX (n = 138) or standard supervised methadone treatment (n = 134). We examined associations between highest BUP-NX and methadone doses, and (1) percentage of opioid-positive urine drug screens (UDS); (2) retention in the assigned treatment; and (3) adverse events (AEs). The mean (SD) highest BUP-NX and methadone dose were 17.31 mg/day (8.59) and 67.70 mg/day (34.70). BUP-NX and methadone doses were not associated with opioid-positive UDS percentages or AEs. Methadone dose was associated with higher retention in treatment (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.010; 1.041), while BUP-NX dose was not (OR: 1.055; 95% CI: 0.990; 1.124). Higher methadone doses (70-110 mg/day) offered higher odds of treatment retention. Methadone dose was associated with higher retention, which may be related to its full µ-opioid receptor agonism. Future research should notably ascertain the effect of pace of titration on a wide range of outcomes. Our results extend previous findings of high doses of methadone increasing retention to be applied in our population using opioids other than heroin, including highly potent opioids.


Design of solid-core microstructured optical fiber with steering-wheel air cladding for optimal evanescent-field sensing.
We present the design of a solid-core microstructured optical fiber with steering-wheel pattern of large holes in cladding as platform for evanescent-field sensing. Both geometry and optical properties of the fiber are numerical computed and analyzed in consideration of manufacturability using sol-gel casting technique as well as by evaluating a triangular lattice of holes with three rings in the design structure so that effective parameters can be established using effective step-index model. We predict less than 0.7 dB/m confinement loss at 850 nm, 29%, 13.7%, and 7.2% of light intensity overlap in air holes at 1500 nm, 1000 nm, and 850 nm wavelength, respectively, in such fiber. With the low loss and high mode-field overlap, the steering-wheel structured fiber is well suited for evanescent-field sensing and detection of chemical and biological species.


Transport of solar wind into Earth's magnetosphere through rolled-up Kelvin-Helmholtz vortices.
Establishing the mechanisms by which the solar wind enters Earth's magnetosphere is one of the biggest goals of magnetospheric physics, as it forms the basis of space weather phenomena such as magnetic storms and aurorae. It is generally believed that magnetic reconnection is the dominant process, especially during southward solar-wind magnetic field conditions when the solar-wind and geomagnetic fields are antiparallel at the low-latitude magnetopause. But the plasma content in the outer magnetosphere increases during northward solar-wind magnetic field conditions, contrary to expectation if reconnection is dominant. Here we show that during northward solar-wind magnetic field conditions-in the absence of active reconnection at low latitudes-there is a solar-wind transport mechanism associated with the nonlinear phase of the Kelvin-Helmholtz instability. This can supply plasma sources for various space weather phenomena.


Grief, Social Support, Spirituality, and Depressive Symptoms Among Older Adults in Assisted Living in Kansas.
The purpose of this study was to explore the roles of grief, social support, as well as spirituality on the depressive symptoms of older adults in assisted living in Kansas. This study tested three hypotheses: a high level of grief will be related to a high level of depressive symptoms; high levels of social support (family, friends, and significant persons) will be associated with a low level of depressive symptoms; and high levels of spiritual experience and coping will be associated with a low level of depressive symptoms. This study recruited 316 older adult residents aged 65 or over from seven assisted living facilities in Kansas. This cross-sectional survey was done by face-to-face interviews using the purposive sampling method. Hierarchical multiple regression was used to test the three sets of variables in relation to depressive symptoms: socio-demographics, social support factors, and spiritual factors. Participants' mean age was 82.6 years, ranging from 65 to 102; 70.9% were female. Married participants consisted of 18.7%, and over 64% were widowed. Hierarchical multivariate regression results indicated that a high level of grief was significantly related to a high level of depressive symptoms. On the other hand, high levels of social support from friends and spiritual coping were significantly associated with a low level of depressive symptoms. Assisted living facilities may consider developing appropriate bereavement, social support, and spiritual intervention programs, which will alleviate the depression issues of older adult residents after the COVID-19 pandemic.