Verbal intellectual and verbal memory performance of youths with childhood-onset insulin-dependent diabetes mellitus.
Tested the hypothesis that memory dysfunction mediated the decline in verbal intellectual performance (as measured by the WISC-R Vocabulary test) that we detected previously in a prospective study of children who developed IDDM between the ages of 8 to 13 years. Three tests of verbal learning and memory were administered to 57 diabetic youths at end-of-study who had been followed for 8 years, on average. Memory performance at end-of-study was predicted only by Vocabulary test score at study entry. IDDM duration, long-term metabolic control, depression/anxiety, demographic variables, or blood glucose level at the time of assessment were not associated with memory test scores. Stepwise multiple regression revealed that level of performance on a test of short-term or working memory was associated with magnitude of decline in verbal intellectual performance over time, providing partial support for our hypothesis.


Risk factors of lymph node metastasis in lung squamous cell carcinoma of 3 cm or less in diameter.
Through literature review we cannot find an efficient risk factor of lymph node metastasis in lung squamous cell carcinoma (SCC). This study aimed to investigate the risk factors of pathological lymph node status in patients with lung SCC of 3 cm or less in diameter, to provide some reference for the fellow surgeons in the decision of operative option.In total, we analyzed 154 patients with lung SCC of 3 cm or less in diameter who underwent lobectomy or bilobectomy or pneumonectomy with systematic lymph node dissection. The relationship between lymph node status and clinical characteristics were examined.Lymph node metastases were present in 48 patients (31.2%) of the study subjects. Multivariate analysis indicated that, age <60 years old (P = .007), tumor location of central-type (P = .003), tumor long axis >2 cm but ≤3 cm (P = .047) were associated with lymph node metastasis, and their odd ratios (OR) were 3.120, 3.359, and 5.196, respectively. Group analysis of the 74 peripheral lung SCC showed that those with the tumor long axis ≤2 cm had a lower rate of lymph node metastasis (7.9% vs 27.8%, P = .025).Age <60 years old, tumor location of central-type, and tumor long axis >2 cm but ≤3 cm are risk factors of lymph node metastasis in lung SCC. Systematic lymph node dissection or sampling is recommended when tumor central-type location and/or long axis >2 cm in lung SCC are present.


Autoimmune cholangiopathy associated with systemic lupus erythematosus.
We report a 39-year-old female who presented over 11 years with autoimmune cholangiopathy associated with kaleidoscopic manifestations of systemic lupus erythematosus (SLE), including, arthritis, skin changes, pleuritis, diffuse proliferative glomerulonephritis, lymphadenopathy, splenomegaly, hyperglobulinemia, and major depression. While antimitochondrial antibodies (AMA) were absent, antinuclear (ANA) and anti-DNA antibodies were detected in high titres associated with hypocomplementemia. The patient also had vitamin B12 deficiency and antiphospholipid antibodies. The patient required steroids and repeated courses of cyclophosphamide for the management of lupus nephritis, and ursodeoxycholic acid (ursolite) administration resulted in amelioration of cholestatic laboratory abnormalities. This unusual case report and review of literature illustrate that immune liver disease may be an important clinical manifestation of SLE, especially autoimmune cholangiopathy.


[Characteristics of hydrogen and oxygen isotopes in precipitation and moisture sources in Gaoyou, Jiangsu Province, China].
It is necessary to examine the characteristics of hydrological cycle in Gaoyou area of Jiang-su Province in response to climate change and flood disasters. In this study, 121 atmospheric rain samples were collected and environmental factors were recorded from July 2015 to October 2017. We analyzed the hydrogen and oxygen stable isotopic composition of rain and identify moisture sources in this area. Results showed that the hydrogen and oxygen isotopic composition of rain had an seasonal variation, which was positive in the winter but negative in the summer. D-excess value was higher in winter than that in summer. On the annual scale, significantly negative relationships between δD (δ18O) and temperature and between δD (δ18O) and precipitation indicated the "anti-temperature effect" and "precipitation amount effect", respectively. On the seasonal scale, there was no obvious "temperature effect" but "precipitation amount effect" in autumn and winter. Results from the HYSPLIT model showed that the precipitation in this area came mainly from ocean evaporation that was influenced by the Chinese South Sea, Indian Ocean and Pacific Ocean. Precipi-tation in other seasons mainly came from the water vapor mixture from the Eurasian continent, Atlantic Ocean, Arctic Ocean, as well as local evaporation. The seasonal pattern of δD and δ18O values in precipitation was mainly influenced by monsoon activity and El Niño-Southern Oscillation (ENSO). In addition, the precipitation isotopes clearly indicated the shift in climates from El Niño to La Niña.


Cognitive behavior and sensory function were significantly influenced by restoration of active ovarian function in postreproductive mice.
In mammals, the relationship between reproductive function and health has been particularly difficult to define. Previously, in old, postreproductive-aged mice, replacement of senescent ovaries with new ovaries from young, actively cycling mice increased life span. We hypothesized that the same factors that increased life span would also influence health span. In the current experiments, we tested two of the seven domains of function/health, sensory function and cognition to determine if exposure of postreproductive female mice to young transplanted ovaries influenced health span. We evaluated control female CBA/J mice at six, 13 and 16months of age. Additional mice received new (60d) ovaries at 12 or 17months of age and were subsequently evaluated at 16 or 25months of age, respectively. Evaluation of sensory function included two measures of olfactory perception; olfactory identification (buried pellet test) and olfactory discrimination (novel recognition block test). We found a significant age-related decline in olfactory identification in 16-month old mice. This decline was avoided by ovarian transplantation at 12months of age. The olfactory discrimination block test revealed an age-associated increase in time spent on both the novel and familiar blocks. This trend was reversed in 16-month old new-ovary recipients. We evaluated cognitive behavior with a burrowing behavior test. We detected a significant age-related decrease in burrowing behavior at 16months of age. This age-related decrease in burrowing behavior was prevented by ovarian transplantation at 12months of age. In summary, we have shown that cognitive behavior and sensory function, which are negatively influenced by aging, can be positively influenced or restored by re-establishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.


Evaluating the Impact of Telemedicine Expansion on Visit Frequency for Children with Type 1 Diabetes at a Single Academic Center in Oregon.
Objective: The telemedicine expansion (TE) that accompanied the COVID-19 pandemic presents a novel opportunity to increase access to care for rural-residing children with type 1 diabetes (T1D) who may live a great distance from their provider. The study objective was to compare trends in visit frequency among the pediatric T1D population at a single academic center in Oregon before and after TE by those living <100 miles versus ≥100 miles from clinic (MFC) and those residing in urban versus rural areas. Research Design and Methods: We evaluated electronic health record data from 790 children receiving care between July 2018 and December 2021. We estimated differences in likelihood of adequately timed monitoring care (ATMC) over time by patient residence using Generalized Estimating Equations. Results: Just before TE, 37.3% of children were receiving ATMC and those living ≥100 MFC were 20.6% less likely to receive ATMC compared with those living <100 MFC (relative risk [RR] 0.79; confidence interval [95% CI]: 0.57-1.11). Following TE, decreases in ATMC for those living ≥100 MFC were less than for those living <100 MFC (RR of interaction: 1.17; 95% CI: 0.68-2.00). Just before TE, those living in rural areas were as likely to receive ATMC compared with those living in urban areas (RR 1.00; 95% CI: 0.61-1.63). Following TE, decreases in ATMC were greater for those living in rural areas versus urban areas (RR of interaction: 0.79; 95% CI: 0.31-2.01). Conclusions: Between July 2020 and December 2021, the likelihood of ATMC decreased across the entire pediatric T1D population. Decreases in ATMC during this period were more substantial for those living <100 MFC and/or in rural areas, however, these discrepancies were not statistically significant.


Cholelithiasis and cholecystitis in childhood.
Six cases of cholecystitis and cholelithiasis confirmed by x-ray examination and surgical operation were observed in a ten-year period. Due to the wide variability in signs and symptoms in children, cholecystitis and cholelithiasis can be diagnosed only with a high degree of clinical suspicion and roentgenological examination. Gallbladder disease is uncommon in childhood but should be considered in children with vague abdominal pains or bouts of unexplained jaundice. If a normal appendix is found at laparotomy in the "acute abdomen," the surgeon would be wise to palpate other specific organs within the abdomen, including the liver and gallbladder. The treatment of choice is cholecystectomy. The prognosis for recovery is excellent if there is no complicating systemic disease.


Distinct dual antiviral mechanism that enhances hepatitis B virus mutagenesis and reduces viral DNA synthesis.
Reverse transcriptase (RT) is an essential enzyme for the replication of retroviruses and hepadnaviruses. Current therapies do not eliminate the intracellular viral replication intermediate termed covalently closed circular (ccc) DNA, which has enhanced interest in hepatitis B virus (HBV) reverse transcription and cccDNA formation. The HBV cccDNA is generated as a plasmid-like episome in the host cell nucleus from the protein-linked relaxed circular (rc) DNA genome in incoming virions during HBV replication. The creation of the cccDNA via conversion from rcDNA remains not fully understood. Here, we sought to investigate whether viral mutagens can effect HBV replication. In particular, we investigated whether nucleoside analogs that act as viral mutagens with retroviruses could impact hepadnaviral DNA synthesis. We observed that a viral mutagen (e.g., 5-aza-2'-deoxycytidine, 5-aza-dC or 5-azacytidine, 5-aza-C) severely diminished the ability of a HBV vector to express a reporter gene following virus transfer and infection of target cells. As predicted, the treatment of 5-aza-dC or 5-aza-C elevated the HBV rcDNA mutation frequency, primarily by increasing the frequency of G-to-C transversion mutations. A reduction in rcDNA synthesis was also observed. Intriguingly, the cccDNA nick/gap region transcription was diminished by 5-aza-dC, but did not enhance viral mutagenesis. Taken together, our results demonstrate that viral mutagens can impact HBV reverse transcription, and propose a model in which viral mutagens can induce mutagenesis during rcDNA formation and diminish viral DNA synthesis during both rcDNA formation and the conversion of rcDNA to cccDNA.


Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy.
Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNALeu(UUR) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD+/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD+/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease.


"Now I Can Do Better": A Study of Obese Women's Experiences Following a Nonprescriptive Nutritional Intervention.
The present study analyzed obese women's experiences following a nonprescriptive nutritional intervention, implemented through a 1-year program based on the Health at Every Size(®) philosophy. We employed an action research method and conducted three focus groups during the intervention. We identified five interpretative axes across the focus groups, as follows: conflicts and perceptions; gaining motivation, perspective, and positioning; becoming autonomous eaters; acquiring tools; and the meetings between the nutritional therapist and participant. Our findings revealed varying levels of readiness among participants in adapting to the intervention and varying valuations of achievements related to eating and health, independent of body-weight changes. Participants reported benefiting from and expressed approval of the intervention. Participants reported positive behavioral and attitudinal changes to their diet and improvements to diet quality, diet structure, and consumption. Finally, participants seemed to show increased autonomy concerning diet and indicated increased confidence, comfort, flexibility, and positivity of attitude regarding eating.


Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis.
Lymph node metastasis (LNM) is common in papillary thyroid cancer (PTC), and is an indicator of recurrence. The detailed molecular mechanism of LNM in PTC has not been well described. This study aimed to investigate the role of fibronectin 1 in PTC LNM and its clinical relevance. The expression of fibronectin 1 was confirmed in PTC tissues and cell lines. A correlation analysis was conducted and a receiver-operating characteristic curve obtained. The effect of fibronectin 1 on the proliferation of PTC cell lines was performed using a colony-formation assay and Cell Counting Kit 8. Cell-cycle analysis was performed with a flow-cytometry assay. Migration and invasion ability were evaluated by transwell and wound-healing assays. Fibronectin 1 was overexpressed in metastasized PTC. Overexpressed fibronectin 1 was positively correlated with PTC LNM. Receiver-operating characteristic analysis showed that the diagnostic accuracy of fibronectin 1 was 81.1%, with sensitivity of 80% and specificity of 82%. Overexpression of fibronectin 1 promoted proliferation, migration, and invasion in PTC. Fibronectin 1 plays a critical role in PTC metastasis by modulating the proliferation, migration, and invasion ability of PTC cells, and it is a valuable diagnostic biomarker for predicting PTC LNM.


[Intraoperative (hyperthermic) intraperitoneal chemotherapy--considerations and aspects of safe intra- and postoperative treatment with cytostatic drugs].
The application of open intraoperative intraperitoneal chemotherapy following cytoreductive surgery for the treatment of pseudomyxoma peritonei or peritoneal carcinomatosis requires safety precautions for the medical and non-medical personnel. In agreement with already existing rules, precautions were established which result in an optimum of safety. These concern the preparation of the cytostatic drugs, the application in the operating room as well as personal precautions intra- and postoperatively. After the establishment of theses recommendations, 22 patients were treated with open intraperitoneal chemotherapy in 1.5 years without any severe accidents. Therefore, a safe intraoperative use of cytotoxic drugs is possible. At the moment, the indication for such an approach may be given in peritoneal carcinomatosis from appendix, colon or ovarian cancer. In the future, an adjuvant application in other gastrointestinal malignancies (e.g. T3/T4 gastric carcinoma) may be considered.


Social relationships, living arrangements and loneliness.
Oldest-old people are expected to be particularly likely to experience loneliness due to the loss of their intimate partner or of same-aged social network members. It is assumed that individuals in different living arrangements maintain different kinds of social networks because they adjust their networks to their specific needs. However, not much is known about the variation in the social networks of the oldest-old depending on their living arrangements and how this variation is related to loneliness. This is the first study that seeks to fill this research gap by examining how the composition and the size of a social network varies among the oldest-old depending on their living arrangements with a partner (coresidential partnership, living apart together (LAT) partnership, no partnership), and how this variation contributes to explain loneliness among the oldest-old. We used cross-sectional data from the representative survey NRW80+ (Quality of Life and Well-Being of the Very Old in North-Rhine Westphalia). The sample of analysis used in this study consists of 1860 respondents from the German state of North-Rhine Westphalia aged 80 years and older. Associations between social network characteristics and living arrangements were tested using χ2-tests and one-way ANOVA. Ordered logit models were used to explain loneliness. Respondents in a coresidential partnership maintained larger social networks than those in an LAT partnership and those with no intimate partner. Furthermore, the respondents with no partner maintained more diverse social networks. Compared to those in the other living arrangements, the respondents in an LAT partnership maintained the smallest and least diverse social networks. Being in a coresidential partnership and the social network size were found to be negatively associated with loneliness. First, the results indicate that respondents who do not have a partner adjusted their social networks to meet their needs in the absence of this relationship. Second, we conclude that being in a coresidential partnership and having a large social network protects the oldest-old against loneliness.


Developing clinical leadership in New Zealand hospice staff nurses.
Staff nurse clinical leadership is a relatively new concept that includes the elements of collaboration, coordination, patient advocacy, and often quite autonomous decision-making required of palliative care nurses. Staff nurses need structural and psychological empowerment to develop as clinical leaders. The aim of this study was to establish baseline data regarding the self-perceived structural and psychological empowerment experienced by New Zealand hospice staff nurses and their ability to practise as clinical leaders. An explanatory sequential mixed-methods design was used, which included questionnaires measuring structural and psychological empowerment and clinical leadership behaviours and focus group discussions. Survey respondents reported that they were moderately psychologically and sometimes or rarely structurally empowered and felt that they can practise as clinical leaders most of the time. Two themes were identified from the focus groups. New Zealand staff hospice nurses felt that-despite feeling only moderately psychologically empowered, and only sometimes or rarely structurally empowered-they practise as clinical leaders most of the time.


The association between arterial stiffness and cancer occurrence: Data from Kailuan cohort study.
This study aimed to investigate whether increased arterial stiffness, measured by brachial-ankle pulse wave velocity (baPWV) is associated with cancer. A total of 45,627 Chinese adults underwent a baPWV examination. The participants were followed up from 1st January 2012 to 31st December 2018. Cox proportional hazards model was used to assess the association between the baPWV values and cancer. During a total follow-up duration of 172,775.69 person-years, there were 553 new cases of cancer. The subjects in the highest baPWV group showed an increased risk of cancer when compared with the lowest baPWV group as confirmed by multivariate-adjusted hazard ratios (HR = 1.51, 95% CI = 1.14∼2.00) in the entire cohort. Compared with participants in the lowest baPWV group, the HRs (95% CI) for digestive cancer in the second and third groups were 1.55 (1.00∼2.40) and 1.99 (1.19∼3.33), respectively. The Kaplan-Meier analysis demonstrated a significant increase in cancer in participants with a baPWV ≥ 18 m/s (P < 0.001). Compared with the lowest baPWV group, the highest baPWV group showed an increased risk of cancer in men (HR = 1.72, 95% CI = 1.22∼2.43) and those < 60 years (HR = 1.75, 95% CI = 1.20∼2.55), respectively. Increased arterial stiffness measured by baPWV is associated with cancer occurrence, especially digestive cancer occurrence. ClinicalTrials.gov, identifier ChiCTR-TNRC-11001489.


[Continuous glucose monitoring using the Glucoday system, in children and adolescents who have type one diabetes].
At present times, Continuous Glucose Monitoring is a recommended method to detect glucemia fluctuations in patients who have diabetes, due to the fine correlation between interstitial glucose and capillary glucemia. The objective of this project is obtain a glucose register during a 48 hour period in a group of Type I diabetes patients who have an irregular metabolic control and to evaluate effectiveness of treatment employed, as well as evaluating compliance of the therapeutic norms established for each patient. At the same time, the authors plan to test the usefulness of a graphical register for diabetic education. After applying an anesthetic cream in the lateral umbilical zone, a subcutaneous catheter connected to a GLUCODAY, Menarini Diagnostics glucose sensor is inserted which, by means of a continuous sequence taking measures in interstitial liquid, registers a value every three minutes for as long as this connection is maintained. After a maximum 48 hour period, data are transferred to a computer and by means of the corresponding computer program, a graphic register for each patient is produced. Informed consent has been obtained from each patient. There were 23 patients in this study group, each diagnosed to have Type I diabetes; eight of these patients, two girls and six boys, were pre-puberty aged while 15, six girls and nine boys, were adolescents. Two of the pre-puberty patients had pathological antecedents, in one case celiac and the other thyroid disease. Two of the puberty aged patients had a history of chronic lymphocytic thyroid disease under opo-therapeutic treatment. Individual analysis of each case permits health professionals to detect a series of facts: it is difficult to comply with glucemic objectives in this group of adolescents having diabetes, with insulin treatment installed and researchers detect postprandial hyper-glucemia which do not appear when using capillary glucemias carried out by habitual methods. Study observations manifest a lack of compliance in indicated agreed upon schedules and researchers detect dietary transgressions. Continuous Glucose Monitoring makes it possible to obtain a graphic which can include those incidences which have occurred, facilitate commenting on the errors detected with adolescent patients and permit proposing a series of therapeutic modifications based on concrete, real data. Continuous Glucose Monitoring promises to be a useful tool to educate patients about diabetes.


Erythrocyte glutathione transferase. A sensitive Up-Down biomarker of environmental and industrial pollution.
Erythrocyte glutathione transferase is a well-known biomarker of environmental pollution. Examination of the extensive scientific literature discovers an atypical and very interesting property of this enzyme which may reveal a chronic exposition to many contaminants but in some cases even an acute and short-term dangerous contamination. This review also underlines the peculiar molecular and kinetic properties of this enzyme which makes it unique in the panorama of enzymes used as biomarker for environmental contamination.


Comparison of results of 500 microdiscectomies and 500 percutaneous laser disc decompression procedures for lumbar disc herniation.
This article aimed to analyze the neurosurgical results of 500 patients treated with microdiscectomies and 500 patients treated with percutaneous laser disc decompression. It has been suggested in the literature that percutaneous laser disc decompression might be considered a serious and valid alternative to microdiscectomy in the treatment of patients with discogenic pain caused by herniated lumbar disc. Patients with herniated discs were treated by microdiscectomy (n = 500) according to the Caspar technique, and patients with discogenic pain were treated with percutaneous laser disc decompression (n = 500) according to the Choy technique. The inclusion and exclusion criteria were the same for both groups of patients. Age, gender distribution, multiple levels involved, and associated pathologies were not statistically different. The results were evaluated for both groups with the MacNab criteria. The follow-up period was 2 years (+/-1 year). In the microdiscectomy group, 85.6% of patients (n = 428) had a good or excellent outcome; in the percutaneous laser disc decompression group, 83.8% of patients (n = 419) had a good or excellent outcome. Complications occurred in 2.2% (n = 11) in the microdiscectomy group and in 0% in the percutaneous laser disc decompression group. The analysis of results for the two groups supports the conclusion that percutaneous laser disc decompression is a safe, minimally invasive, and strong alternative treatment to microdiscectomy in patients affected by herniated discs.


[Effect of moxibustion intervention on expression of gastric epidermal growth factor receptor and extracellular signal regulated kinase 1/2 expression in rats with gastric ulcer].
To observe the effect of moxibustion on epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase 1/2(p-ERK1/2) protein expression in gastric ulcer (GU) rats so as to reveal its mechanisms underlying improving GU. Fifty SD rats were randomly allocated to control,model, medication ("Sijunzi" Decoction), non-acupoint moxibustion (non-acup-moxi), and acup-moxi groups (n=10 in each group). The GU model was established by intragastric perfusion of absolute alcohol. Rats of the control group were treated by gavage of distilled water. Rats of the medication group were treated by administration of "Sijunzi" Decoction (8 mL x kg(-1) d(-1)),twice a day for 8 days. Moxibustion intervention was applied to bilateral "Zusanli" (ST 36),"Zhongwan" (CV 12),and "Pishu" (BL 20), "Weishu" (BL 21) alternatively for 30 min, once daily for 8 days. The animals' ulcer index (UI) was assessed by Guth's method, and gastric mucosal pathological changes were observed under light microscope following H. E. staining. The expression of gastric EGFR was detected by immunohistochemistry and that of phosphorylated ERK1/2 (p-ERK1/2) protein determined by Western blot. Compared with the control group, the UI, gastric EGFR and p-ERK1/2 protein expression levels were significantly increased in the model group(P<0.01, P<0.05); whereas in comparison with the model group, the UI was notably decreased in the medication, non-acup-moxi and acup-moxi groups (P<0.05, P<0.01), and EGFR and p-ERK1/2 protein expression levels were further up-regulated in the three treatment groups (P<0.01). The effects of both medication and acup-moxi groups were obviously superior to those of the non-acup-moxi group (P<0.01, P<0.05). No significant differences were found between the medication and acup-moxi groups in the expression levels of EGFR and p-ERK1/2 proteins (P>0.05). Results of H.E. staining showed that alcohol-induced gastric mucosal injury as breakage, exfoliation, inflammatory cell infiltration, etc. was milder in both medication and acup-moxi groups following the treatment. Acupoint-moxibustion has a role in relieving alcohol induced gastric mucosal injury in the rat, which may be closely associated with its effects in up-regulating activities of the EGFR/ERK signal transduction pathway.


Diagnostic yield of early repeat colonoscopy after suboptimal bowel preparation in a fecal immunochemical test-based screening program.
Current guidelines regarding surveillance after screening colonoscopy assume adequate bowel preparation. However, follow-up intervals after suboptimal cleansing are highly heterogeneous. We aimed to determine the diagnostic yield of early repeat colonoscopy in patients with suboptimal bowel preparation in fecal immunochemical test (FIT)-based screening colonoscopy. An observational study including patients who underwent colonoscopy with suboptimal bowel preparation after positive FIT screening and then repeat colonoscopy within 1 year. Suboptimal preparation was defined as a Boston Bowel Preparation Scale (BBPS) score of 1 in any segment. Patients with a BBPS score of 0 in any segment or incomplete examination were excluded. The adenoma detection rate (ADR), advanced ADR (AADR), and colorectal cancer rate were calculated for the index and repeat colonoscopies. Of the 2474 patients with FIT-positive colonoscopy at our center during this period, 314 (12.7 %) had suboptimal preparation. Of the 259 (82.5 %) patients who underwent repeat colonoscopy, suboptimal cleansing persisted in 22 (9 %). On repeat colonoscopy, the ADR was 38.7 % (95 %CI 32.6 % to 44.8 %) and the AADR was 14.9 % (95 %CI 10.5 % to 19.4 %). The per-adenoma miss rate was 27.7 % (95 %CI 24.0 % to 31.6 %), and the per-advanced adenoma miss rate was 17.6 % (95 %CI 13.3 % to 22.7 %). After repeat colonoscopy, the post-polypectomy surveillance recommendation changed from 10 to 3 years in 14.7 % of the patients with previous 10-year surveillance recommendation. Patients with suboptimal bowel preparation on FIT-positive colonoscopy present a high rate of advanced adenomas in repeat colonoscopy, with major changes in post-polypectomy surveillance recommendations.


[Impact of allergic rhinitis on work productivity: a pilot study].
Allergic rhinitis can interfere with cognitive function, can impair work productivity, and may cause work absences. In this study, we evaluated the impact of Japanese cedar pollinosis (JCP) on work productivity. The study was conducted between February 24 and March 8, 2003 (peak pollen season), and 512 workers with JCP were enrolled. Study outcomes included self-reported work productivity (absenteeism and presenteeism) and quality of life (the Medical Outcomes Study Short Form-36). Most patients (91%) did not lose their work time due to JCP during the past 7 days. Approximately half of patients reported a 25% reduction in productivity compared with non pollination season. In multiple logistic regression analysis, the following factors were selected as independent risk factors for lost work time: duration of disease (adjusted odds ratio (aOR) = 0.658) and itching eyes (aOR = 1.552). Likewise, SF-36 PCS (aOR = 0.946), MCS (aOR = 0.927) and using pollinosis relief products (aOR = 2.020) were predictors of lost productivity. This study shows that we should pay more attention to ocular symptoms as well as nasal symptoms and improve patients' quality of life as soon as possible in order to reduce productivity losses.


Biomechanical Comparison of Dart-Throw Motions after Partial Wrist Fusions.
Background Multiple partial wrist fusions exist for the management of arthritic disease. Limited information is available on their effect on wrist range of motion in the dart-throwing direction of wrist motion, even though it is used in most activities of daily living. Purpose The purpose of this study was to measure the retained motion for different orientations of dart-throwing motion for seven different partial wrist fusions and proximal row carpectomy (PRC). Methods Eight fresh frozen right cadavers were tested with the wrist intact and followed simulated fusions. Fusions were performed using an external fixation technique and included scaphocapitate, scapholunate (SL), capitolunate, radiolunate, radioscapholunate, scaphotrapeziotrapezoid, 4 corner fusion, and PRC. Results In the intact wrist, the average arc of wrist motion with the wrist oriented at 20 degrees away from the flexion-extension axis was significantly larger than at any other orientation of motion. All partial wrist fusions and the PRC had significantly smaller average dart-throw arc of motion compared with intact at an orientation 20 and 25 degrees away from flexion-extension. The SL fusion provided a significantly larger arc of motion than most of the other fusions at most orientations. Conclusion/Clinical Relevance This study provides a comprehensive compilation of the range of motion in a functional plane, "the dart-throw motion," for limited wrist fusions and PRC. These data provide the clinician with important information that can be used to educate patients regarding expectations after surgery.


Effectiveness of rapid antigen testing for screening of asymptomatic individuals to limit the transmission of SARS-CoV-2: A rapid review.
Rapid antigen detection tests (RADTs) offer advantages over gold-standard reverse transcription polymerase chain reaction (RT-PCR) tests in that they are cheaper and provide faster results, thus enabling prompt isolation of positive SARS-CoV-2 cases and quarantine of close contacts. The aim of this study was to collate and synthesise empirical evidence on the effectiveness of rapid antigen testing for the screening (including serial testing) and surveillance of asymptomatic individuals to limit the transmission of SARS-CoV-2. A rapid review was undertaken in MEDLINE (EBSCO), EMBASE (OVID), Cochrane Library, Europe PMC and Google Scholar up until 19 July 2021, supplemented by a grey literature search. Of the identified 1222 records, 19 reports referring to 16 studies were included. Eight included studies examined the effectiveness of RADTs for population-level screening, four for pre-event screening and four for serial testing (schools, a prison, a university sports programme and in care homes). Overall, there is uncertainty regarding the effectiveness of rapid antigen testing for the screening of asymptomatic individuals to limit the transmission of SARS-CoV-2. This uncertainty is due to the inconsistent results, the relatively low number of studies identified, the predominantly observational and/or uncontrolled nature of the study designs used, and concerns regarding methodological quality. Given this uncertainty, more real-world research evidence in relevant settings, which is of good quality and timely, as well as economic evaluation, is required to inform public policy on the widespread use of RADTs in asymptomatic individuals.


Prognostic factors for tumor recurrence in endometrioid endometrial cancer stages IA and IB.
Risk grouping for treatment and follow-up strategy of early stage endometrial cancer is confusing to apply in clinical conditions. We investigated the stage-based prognostic factors for tumor recurrence in stage I endometrial cancer with endometrioid histology (EEC).The medical records of women diagnosed with endometrial adenocarcinoma between 1993 and 2013 were retrospectively reviewed. In 521 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I EEC were included. The baseline patient characteristics were analyzed with the chi-square test and Fisher's exact tests. A multivariate analysis with a Cox proportional hazard model and logistic regression were performed to identify the prognostic factors for recurrence-free survival (RFS) in FIGO stage I EEC.The median follow-up period for the included patients was 74.6 months (3.1-264.9 months). Tumor recurrence occurred in 30 patients (5.8%) with a median time span of 22.85 months (2.2-124.7 months). Only 2 factors among the conventional adverse risk factors, including myometrial invasion and histologic grade, affected tumor recurrence in stage I EEC (P = .003 and P = .003, respectively). Myometrial invasion was an independent prognostic factor for RFS in stage IA EEC via multivariate analysis (P = .005). In stage IB EEC, the histologic grade was an independent prognostic factor for RFS. The median RFS of stage IB EEC was 156.0 months in grade 1, 120.0 months in grade 2, and 105.9 months in grade 3 (P = .006).Within stage I EEC, the prognostic factors for tumor recurrence were different between stages IA and IB. Myometrial invasion comprised the prognostic factor in stage IA, whereas the histologic grade comprised the prognostic factor in stage IB.


The cellular basis for volume changes in the rat cortex during puberty: white and gray matter.
We have found that developmental changes through the adolescent period in the rat cerebral cortex provide parallels to those seen in the human cortex. Like humans, the rat cerebral white matter increases during this time due to increases in the number of axons that become myelinated even while the total number of axons decreases. We have preliminary evidence that estrogen decreases the rate of myelination, which results in a sex difference in adult rats. Another parallel to the human cortex is the nonlinear changes in the size of the cortex. We have found that in some cortical regions, female rats show decreases in cortical volume and number of neurons across the time of puberty, and removal of the ovaries stops these decreases. The rat cortex may serve as a model for the cellular changes underlying the volume changes seen in adolescent humans.


[Isolation, identification and genome sequenceing of a rabbit hemorrhagic disease virus strain WHNRH].
The rabbit hemorrhagic disease virus (RHDV) is a single-stranded positive-sense RNA virus of the family Caliciviridae with a high morbidity and mortality rates of about 90% in adult rabbits. A strain of rabbit hemorrhagic disease virus named WHNRH was isolated and identified in the research. The genome of WHNRH was then sequenced. Primers were designed referring to the genome sequences of RHDV published in GenBank and a RACE was applied to get the 5' terminus sequences. The other terminus sequences of WHNRH was acquired referring to the genome's polyA structure of RHDV. The genome was amplified with RT-PCR. All the RT-PCR products were cloned into the pMD18-T vector and sequenced. The sequencing result indicated that the complete genome of RHDV isolated strain WHNRH was composed of 7437nt (not including polyA of 3' terminus), the identities were between 89.4% and 97.1% compared with the published genome sequences of six RHDV strains. The ORF1 of the genome of WHNRH was between 10nt and 7044nt and a polypeptide with 2344 amino acids was coded, the identities of nucleotide and amino acids sequences were 89.1% - 96.1% and 96.0% - 98.4% respectively compared with the six published RHDV strains. The ORF2 of the genome of WHNRH was between 7025nt and 7378nt and a polypeptide with 177 amino acids was coded, the identities of nucleotide and amino acids sequences were all between 92.1% and 96.9% compared with the six published RHDV strains.


Postoperative fatigue and changes in nutritional status.
Subjective feeling of fatigue was quantified before and 10, 20 and 30 days after elective uncomplicated abdominal surgery in 36 otherwise healthy patients, using a constructed fatigue scale model. One third of the patients had a remarkable increase in fatigue which continued throughout the first postoperative month. The fatigued patients showed a more pronounced postoperative loss in weight (P less than 0.001), triceps skinfold caliper (P less than 0.001) and arm muscle circumference (n.s.) and had lower levels in serum transferrin (P less than 0.02). No correlation was found between postoperative fatigue and postoperative changes in blood haemoglobin, lymphocyte count, plasma albumin, electrolytes and various minerals. Development of late postoperative fatigue was unpredictable from pre-operative nutritional status, serum transferrin, albumin, electrolytes, haemoglobin, lymphocyte count and various minerals, as well as from age, sex and duration of surgery. These results suggest future therapeutic measures against the postoperative fatigue syndrome.


Toward an Ethics of Community-Academic Partnership.
Community-academic partnerships, which often form unexpectedly, can be time consuming, tedious, and sometimes awkward alliances, yet they arise out of perceived needs and can be fruitful. Putting aside hierarchy to explore such partnerships as communities themselves that seek to capitalize on the strengths, knowledge, and life experiences of each stakeholder can offer a fresh perspective for thinking about the ethics of community-academic partnerships. This commentary explores the partnerships detailed in the symposia through the lens of ethnography.


A Direct Test of Selection in Cell Populations Using the Diversity in Gene Expression within Tumors.
Although intratumor diversity driven by selection has been the prevailing view in cancer biology, recent population genetic analyses have been unable to reject the neutral interpretation. As the power to reject neutrality in tumors is often low, it will be desirable to have an alternative means to test selection directly. Here, we utilize gene expression data as a surrogate for functional significance in intra- and intertumor comparisons. The expression divergence between samples known to be driven by selection (e.g., between tumor and normal tissues) is always higher than the divergence between normal samples, which should be close to the neutral level of divergence. In contrast, the expression differentiation between regions of the same tumor, being lower than the neutral divergence, is incompatible with the hypothesis of selectively driven divergence. To further test the hypothesis of neutral evolution, we select a hepatocellular carcinoma tumor that has large intratumor SNV and CNV (single nucleotide variation and copy number variation, respectively) diversity. This tumor enables us to calibrate the level of expression divergence against that of genetic divergence. We observe that intratumor divergence in gene expression profile lags far behind genetic divergence, indicating insufficient phenotypic differences for selection to operate. All these expression analyses corroborate that natural selection does not operate effectively within tumors, supporting recent interpretations of within-tumor diversity. As the expected level of genetic diversity, hence the potential for drug resistance, would be much higher under neutrality than under selection, the issue is of both theoretical and clinical significance.


Molecular genetic defects in congenital hypothyroidism.
Recently molecular genetic defects in some cases of congenital hypothyroidism (CH) as well as of rare cases of central hypothyroidism have been identified. These studies have led to the description of so far unexplained forms of these disorders. In some patients with CH early diagnosis by newborn screening and early treatment was not able to lead to a normal mental development. This could subsequently be explained by molecular defects of transcription factors (FOXE-1/FKHL15, NKX2.1) which are important not only for the embryonic development of the thyroid gland but also for other organs including the central nervous system (CNS). These findings will help in understanding the critical role of thyroid hormones in the pre-and postnatal CNS development. However, many questions regarding the molecular defects and their consequences in the majority of patients with CH still remain open and will be addressed in this article.


Shedding light on trophic interactions: A field experiment on the effect of human population between latitudes on herbivory and predation patterns.
Interactions between species within an ecosystem (e.g. predation and herbivory) play a vital role in sustaining the ecosystem functionality, which includes aspects like pest control and nutrient cycling. Unfortunately, human activities are progressively disrupting these trophic relationships, thereby contributing to the ongoing biodiversity decline. Additionally, certain human activities like urbanization may further impact the intensity of these trophic interactions, which are already known to be influenced by latitudinal gradients. The aim of this study was to test the hypothesis of whether the impact of human population, used as a proxy for human pressure, differs between latitudes. To test it, we selected 18 study sites at two latitudes (i.e. ~53°N and ~50°N) with varying human population density (HPD). We used artificial caterpillars placed on European beech branches to assess bird predation and took standardized pictures of the leaves to estimate insect herbivory. Remote sensing techniques were used to estimate human pressure. We found that the intensity of bird predation varied in response to HPD, with opposite trends observed depending on the latitude. At our upper latitude, bird predation increased with HPD, while the opposite was observed at the lower latitude. Herbivory was not affected by urbanization and we found higher levels of herbivory in the lower compared to the higher latitude. At the lower latitude, certain species may experience a disadvantage attributed to the urban heat island effect due to their sensitivity to temperature fluctuations. Conversely, at the higher latitude, where minimum temperatures can be a limitation, certain species may benefit from milder winters. Overall, this study highlights the complex and dynamic nature of trophic relationships in the face of human-driven changes to ecosystems. It also emphasizes the importance of considering both human pressure and latitudinal gradients when assessing the ecological consequences of future climate change scenarios, especially in urban environments.


Biosolids and Sludge Management.
This review section covers journal articles and conference papers related to biosolids and sludge management that were published in 2014. The literature review has been divided into the following sections: • Biosolids regulations and management issues; • ;Biosolids characteristics, quality and measurement including microconstituents and pathogens; • Sludge treatment technologies including pretreatment and sludge minimization, conditioning and dewatering, digestion, composting and innovative technologies; • Disposal and reuse including combustion/ incineration, land application and non- agricultural use; • Odor and air emissions; and • Energy issues.


The Efficacy of Probiotics for Treatment of Bipolar Disorder-Type 1: A Randomized, Double-Blind, Placebo Controlled Trial.
Objective: Bipolar disorders are among the most common chronic mental disorders. Despite the recent improvement in controlling psychiatric disorders, treatment of bipolar disorders remains a challenge. The aim of this study was to determine the effect of consuming probiotics in patients with bipolar disorder-type 1 compared to the placebo group. Method : This was a permuted blocked randomized clinical trial conducted in Shahid Beheshti mental hospital in Kerman, Iran, from October 2017 to October 2018. Two psychiatrists diagnosed and hospitalized all 38 patients with type 1 bipolar disorder based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Using blind randomized blocking method size 4, patients were divided into 2 groups of placebo and probiotic. Young Mania Rating Scale (YMRS) and Hamilton's Depression Rating Scale (HDRS) were completed at the beginning, week 4, and week 8 of the study by a psychiatry resident. Independent t test, Mann-Whitney and repeated measures ANOVA tests were used. Data were analyzed using SPSS software version 20. Results: There was no significant difference between the 2 groups in age, sex, and severity of mania and depression. Consumption of probiotics reduced the scores of YMRS and HDRS over time in the probiotic group more than the placebo group, but it was not significant. Conclusion: Consumption of probiotics had non-significant effects on improvement and treatment of bipolar type 1 patients. It is suggested that future studies be conducted with different probiotic microbial strains and longer period of treatment.


CIHR Candrive Cohort Comparison with Canadian Household Population Holding Valid Driver's Licenses.
We investigated whether convenience sampling is a suitable method to generate a sample of older drivers representative of the older-Canadian driver population. Using equivalence testing, we compared a large convenience sample of older drivers (Candrive II prospective cohort study) to a similarly aged population of older Canadian drivers. The Candrive sample consists of 928 community-dwelling older drivers from seven metropolitan areas of Canada. The population data was obtained from the Canadian Community Health Survey - Healthy Aging (CCHS-HA), which is a representative sample of older Canadians. The data for drivers aged 70 and older were extracted from the CCHS-HA database, for a total of 3,899 older Canadian drivers. Two samples were demonstrated as equivalent on socio-demographic, health, and driving variables that we compared, but not on driving frequency. We conclude that convenience sampling used in the Candrive study created a fairly representative sample of Canadian older drivers, with a few exceptions.


RNA synthesis by nuclei and chromatin isolated from adult and senescent Wistar rat liver.
Nuclei isolated from senescent (22-26 months) female Wistar rat liver show a decreased RNA synthesis compared to nuclei from adult (12 months) liver. Kinetic analyses demonstrate a decreased rate (25-42%) and maximal incorporation (41-54%) of labeled uridine triphosphate into both rRNA and mRNA in senescent nuclei. Chromatin-bound RNA polymerase activity is decreased by 36%, whereas free RNA polymerase activity, i.e., not bound to chromatin, is increased by 41% in senescent nuclei, but the total bound plus free activity is the same in senescent and adult nuclei. Isolated senescent chromatin shows reduced transcriptional capacity and requires a higher temperature to initiate melting. A decreased ability of chromatin to bind RNA polymerases appears to underlie the observed decreased RNA synthesis in senescent liver nuclei.


Quality improvement initiative: Preventative Surgical Site Infection Protocol in Vascular Surgery.
Objective A quality improvement initiative was employed to decrease single institution surgical site infection rate in open lower extremity revascularization procedures. In an attempt to lower patient morbidity, we developed and implemented the Preventative Surgical Site Infection Protocol in Vascular Surgery. Surgical site infections lead to prolonged hospital stays, adjunctive procedure, and additive costs. We employed targeted interventions to address the common risk factors that predispose patients to post-operative complications. Methods Retrospective review was performed between 2012 and 2016 for all surgical site infections after revascularization procedures of the lower extremity. A quality improvement protocol was initiated in January 2015. Primary outcome was the assessment of surgical site infection rate reduction in the pre-protocol vs. post-protocol era. Secondary outcomes evaluated patient demographics, closure method, perioperative antibiotic coverage, and management outcomes. Results Implementation of the protocol decreased the surgical site infection rate from 6.4% to 1.6% p = 0.0137). Patient demographics and comorbidities were assessed and failed to demonstrate a statistically significant difference among the infection and no-infection groups. Wound closure with monocryl suture vs. staple proved to be associated with decreased surgical site infection rate ( p < 0.005). Conclusions Preventative measures, in the form of a standardized protocol, to decrease surgical site infections in the vascular surgery population are effective and necessary. Our data suggest that there may be benefit in the incorporation of MRSA and Gram-negative coverage as part of the Surgical Care Improvement Project perioperative guidelines.


Sources in the history of occupational health: the Turner & Newall archive.
Sources in the History of occupational health are scanty-a reflection perhaps of the contentious nature of the documentation. In the UK, asbestos company records have until recently been unavailable and consequently historians and policy-makers have been hindered from exploring a major public health issue. In 1995, however, Chase Manhattan Bank in New York sued the leading British asbestos producer, Turner & Newall, in a property-damage claim. During pre-trial discovery, Chase had copied a large proportion of Turner & Newall's vast archive and under American law was able to put the records in the public domain. This article describes how this collection of records-perhaps the largest anywhere on the history of an occupational health hazard-was generated. It also suggests ways of navigating the documents; discusses the nature of the material; and the archive's uses to medical and industrial historians.


Improved neurobehavioral functioning in emphysema patients following lung volume reduction surgery compared with medical therapy.
The goal of this study was to evaluate the neuropsychological and psychological functioning of emphysema patients following lung volume reduction surgery (LVRS) compared with patients receiving only medical therapy (MT). Patients with moderate-to-severe emphysema who were enrolled in the National Emphysema Treatment Trial at two sites (National Jewish Medical and Research Center and Ohio State University) were given a neuropsychological battery at baseline, 6 to 10 weeks later (following participation in pulmonary rehabilitation), and at 6 months following randomization to either LVRS or MT treatment. Twenty patients randomized to MT, 19 patients randomized to LVRS, and 39 matched, healthy control subjects completed a battery of tests that measured cognitive functioning, depression, anxiety, and quality of life (QoL). Controlling for practice, patients in the LVRS treatment arm at the 6-month follow-up demonstrated significant improvement compared with MT patients in cognitive tasks involving sequential skills and verbal memory. The LVRS patients also showed significant reductions in depression compared with the MT patients, as well as improved physical and psychosocial QoL. Correlational analysis indicated that improved immediate verbal memory in the LVRS group was related to improved QoL. No associations were found between changes in cognitive function and changes in depression, exercise performance, or pulmonary functioning. Patients who received LVRS demonstrated improvement in specific neuropsychological functions, depression, anxiety, and QoL scores compared with patients with continued MT treatment 6 months following randomization. However, mechanisms for these neurobehavioral changes are unclear. Improved verbal memory and sequential skills following LVRS were not directly associated with depression or exercise capacity. Nonetheless, LVRS led to a strong and likely clinically significant improvement in neuropsychological functioning over and above that explained by practice effects or MT. This finding adds to the growing list of clinical benefits of LVRS over MT, and supports additional research into the underlying mechanisms of this therapeutic effect.


Quantification methods for human and large animal leukocytes using DNA dyes by flow cytometry.
Ovine and bovine blood is used heavily within the development of blood-handling medical devices, such as heart pumps (left ventricular assist devices, LVADs), for which blood cell damage needs to be monitored during in vitro testing. Hematology analyzers provide cell counts but no information about cell viability. The anthraquinone DNA dyes CyTRAK Orange™ and DRAQ7™ have practical and spectral properties rendering them suitable for multicolor assays. Compared to other DNA dyes such as Vybrant Dyecycle, CyTRAK Orange enables a faster staining protocol and does not require incubation at +37°C. Compared to traditional viability dyes such as propidium iodide and 7AAD, DRAQ7's unique spectral profile of excitation in both blue and red lasers and far-red emission enables identification of dual positive dead cell events and frees up detectors for use with other reagents. CyTRAK Orange and DRAQ7 could be used in combination with absolute counting bead standards to provide cell counts and viability but the combination of these dyes has previously only been used for microscopy on rodent cells. The purpose of this study was to evaluate the use of these dyes in combination in large animal blood samples for flow cytometry. A viability and cell counting protocol for bovine, ovine, and human leukocytes using CyTRAK Orange and DRAQ7 was prepared. Four different counting bead standards were evaluated using the Navios and FACSAria cytometers and compared to counts obtained from hematology analyzers. CyTRAK Orange successfully detected CD45(+) leukocytes in all species. The DRAQ7 single-stained dead cell counts correlated well with the CyTRAK Orange/DRAQ7 double-stained dead cell counts in human and bovine blood, but not in ovine blood, which could be related to the blood source. In conclusion, for human and bovine blood, this method works well for viability counts using different flow cytometers and bead standards. © 2016 International Society for Advancement of Cytometry.


Cases of Rapid Hepatitis B Surface Antigen Reduction after COVID-19 Vaccination.
Objective One of the therapeutic goals for chronic infection with hepatitis B virus is the clearance of hepatitis B surface antigen (HBsAg) from the blood, as a high load of HBsAg has been proposed to induce antigen-specific immunotolerance. To achieve HBsAg reduction, Pegylated interferon and nucleos (t) ide analogs are used to treat chronic hepatitis B. Following the coronavirus disease 2019 (COVID-19) outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide, and vaccination with mRNA COVID-19 vaccines has been conducted since 2021 in Japan. We experienced three clinical cases in which HBsAg levels rapidly decreased after injection of the COVID-19 vaccine without any incentive. Method To examine whether the vaccine administration was involved in the HBsAg reduction, the number of patients with chronic hepatitis B showing a change in the HBsAg levels during the period before the commencement of the COVID-19 vaccination program in Japan (i.e. until the end of 2020; pre-vaccination-program period) was compared to the number of those who showed a change in HBsAg levels after the initiation of the program (i.e. 2021 onwards; post-vaccination-program period). Results The number of patients whose HBsAg levels was reduced by >50% per year was prominent after the initiation of the vaccination program. Although the involvement of vaccination in HBsAg reduction was not statistically proven (p=0.0532), the result suggests that the administration of COVID-19 vaccines may have been involved in HBsAg reduction in patients with chronic hepatitis B. Conclusion COVID-19 vaccines may be involved in HBsAg reduction.


Early Surgery Prolongs Professional Activity in IDH Mutant Low-Grade Glioma Patients: A Policy Change Analysis.
Until 2015, Dutch guidelines recommended follow-up and biopsy rather than surgery as initial care for suspected low-grade gliomas (LGG). Given evidence that surgery could extend patient survival, our center stopped following this guideline on January 1, 2010 and opted for early maximal safe resection of LGG. The effects of early surgery on the ability of patients to work remains little documented. A total of 104 patients operated on at our center between January 2000 and April 2013 and diagnosed with the WHO 2016 grade 2 astrocytoma, IDH mutant or oligodendroglioma, IDH mutant and deleted 1p19q were included. The clinical characteristics, survival, and work history of patients operated on before or after January 2010 were obtained from the patients' records and compared. The minimal follow-up was 8 years. As per policy change, the interval between radiological diagnosis and first surgery decreased significantly after 2010. Likewise, before 2010, 25.8% of tumors were initially biopsied, 51.6% were resected under anesthesia, and 22.5% under awake conditions versus 14.3%, 23.8%, and 61.9% after this date (p < 0.001). The severity of permanent postoperative neurological deficits decreased after 2010. In total, 82.5% of the patients returned to work postoperatively before 2010 versus 100% after 2010. The postoperative control of epilepsy increased significantly after 2010 (74.4% vs. 47.9%). The median time from diagnosis to a definitive incapacity to work increased by more than 2 years after 2010 (88.7 vs. 62.2 months). A policy shift towards early aggressive surgical treatment of IDH mutant LGG is safe and prolongs the patients' ability to work.


A HOPS Protein, MoVps41, Is Crucially Important for Vacuolar Morphogenesis, Vegetative Growth, Reproduction and Virulence in Magnaporthe oryzae.
The homotypic fusion and protein sorting protein complex (HOPS) is the first known tether complex identified in the endocytic system that plays a key role in promoting homotypic vacuolar fusion, vacuolar biogenesis and trafficking in a wide range of organisms, including plant and fungi. However, the exact influence of the HOPS complex on growth, reproduction and pathogenicity of the economically destructive rice blast fungus has not been investigated. In this study, we identified M. oryzae vacuolar protein sorting 41 (MoVps41) an accessory subunit of HOPS complex and used targeted gene deletion approach to evaluate its contribution to growth, reproduction and infectious life cycle of the rice blast fungus. Corresponding results obtained from this study showed that MoVps41 is required for optimum vegetative development of M. oryzae and observed that MoVps41 deletion mutant displayed defective vegetative growth. Our investigation further showed that MoVps41 deletion triggered vacuolar fragmentation, compromised membrane integrity and pathogenesis of the ΔMovps41 mutant. Our studies also showed for the first time that MoVps41 plays an essential role in the regulation of sexual and asexual reproduction of M. oryzae. In summary, our study provides insight into how MoVps41 mediated vacuolar fusion and biogenesis influences reproduction, pathogenesis, and vacuolar integrity in M. oryzae and also underscores the need to holistically investigate the HOPS complex in rice blast pathogen.


Investigating reproducibility and tracking provenance - A genomic workflow case study.
Computational bioinformatics workflows are extensively used to analyse genomics data, with different approaches available to support implementation and execution of these workflows. Reproducibility is one of the core principles for any scientific workflow and remains a challenge, which is not fully addressed. This is due to incomplete understanding of reproducibility requirements and assumptions of workflow definition approaches. Provenance information should be tracked and used to capture all these requirements supporting reusability of existing workflows. We have implemented a complex but widely deployed bioinformatics workflow using three representative approaches to workflow definition and execution. Through implementation, we identified assumptions implicit in these approaches that ultimately produce insufficient documentation of workflow requirements resulting in failed execution of the workflow. This study proposes a set of recommendations that aims to mitigate these assumptions and guides the scientific community to accomplish reproducible science, hence addressing reproducibility crisis. Reproducing, adapting or even repeating a bioinformatics workflow in any environment requires substantial technical knowledge of the workflow execution environment, resolving analysis assumptions and rigorous compliance with reproducibility requirements. Towards these goals, we propose conclusive recommendations that along with an explicit declaration of workflow specification would result in enhanced reproducibility of computational genomic analyses.


Temporal bone pathology of metastatic T-cell lymphoma.
Metastatic lymphoma involving the temporal bone is a rare tumour. A review of the English literature revealed only 13 reported cases. The common metastatic sites within the temporal bone are bone marrow and the internal auditory canal (IAC). Non-Hodgkin lymphoma has a tendency to infiltrate to the inner ear and middle ear, with bone marrow involvement. Recent advances in immunology have redefined the malignant lymphoma as a neoplasm of the immune system that has involved T and B cells. We present a case of non-Hodgkin T-cell lymphoma that metastasized to the temporal bone and central nervous system.


A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial.
Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset. Hypothesis-generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for fluid-attenuated inversion recovery (FLAIR) hyperintensity in diffusion-positive regions. Reader-measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by coregistration. Lesion conspicuity increased with time on FLAIR (P=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k=0.7091; 95% CI, 0.61-0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59; 95% CI, 0.47-0.71). Reader-measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value=0.90). The SIR was greater for right hemisphere lesions (P=0.04) for a given reported time from stroke symptom onset. The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image coregistration for thrombolytic trial enrollment is not necessary. A SIR <1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.


DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas.
Recurrence rates after breast-conserving therapy may depend on genomic characteristics of cancer-adjacent, benign-appearing tissue. Studies have not evaluated recurrence in association with multiple genomic characteristics of cancer-adjacent breast tissue. To estimate the prevalence of DNA defects and RNA expression subtypes in cancer-adjacent, benign-appearing breast tissue at least 2 cm from the tumor margin, cancer-adjacent, pathologically well-characterized, benign-appearing breast tissue specimens from The Cancer Genome Atlas project were analyzed for DNA sequence, copy-number variation, DNA methylation, messenger RNA (mRNA) sequence, and mRNA/microRNA expression. Additional samples were also analyzed by at least one of these genomic data types and associations between genomic characteristics of normal tissue and overall survival were assessed. Approximately 40% of cancer-adjacent, benign-appearing tissues harbored genomic defects in DNA copy number, sequence, methylation, or in RNA sequence, although these defects did not significantly predict 10-year overall survival. Two mRNA/microRNA expression phenotypes were observed, including an active mRNA subtype that was identified in 40% of samples. Controlling for tumor characteristics and the presence of genomic defects, this active subtype was associated with significantly worse 10-year survival among estrogen receptor (ER)-positive cases. This multi-platform analysis of breast cancer-adjacent samples produced genomic findings consistent with current surgical margin guidelines, and provides evidence that extratumoral RNA expression patterns in cancer-adjacent tissue predict overall survival among patients with ER-positive disease.


The impact of visualization paradigms on the detectability of spatial misalignment in mixed reality surgical guidance.
Mixed reality (MR) for image-guided surgery may enable unobtrusive solutions for precision surgery. To display preoperative treatment plans at the correct physical position, it is essential to spatially align it with the patient intra-operatively. Accurate alignment is safety critical because it will guide treatment, but cannot always be achieved for varied reasons. Effective visualization mechanisms that reveal misalignment are crucial to prevent adverse surgical outcomes to ensure safe execution. We test the effectiveness of three MR visualization paradigms in revealing spatial misalignment: wireframe, silhouette, and heatmap, which encodes residual registration error. We conduct a user study among 12 participants and use an anthropomorphic phantom mimicking total shoulder arthroplasty. Participants wearing Microsoft HoloLens 2 are presented with 36 randomly ordered spatial (mis)alignments of a virtual glenoid model overlaid on the phantom, each rendered using one of the three methods. Users choose whether to accept or reject the spatial alignment at every trial. Upon completion, participants report their perceived difficulty while using the visualization paradigms. Across all visualization paradigms, the ability of participants to reliably judge the accuracy of spatial alignment was moderate (58.33%).The three visualization paradigms showed comparable performance. However, the heatmap-based visualization resulted in significantly better detectability than random chance ([Formula: see text]). Despite heatmap enabling the most accurate decisions according to our measurements, wireframe was the most liked paradigm (50 %), followed by silhouette (41.7 %) and heatmap (8.3 %). Our findings suggest that conventional mixed reality visualization paradigms are not sufficiently effective in enabling users to differentiate between accurate and inaccurate spatial alignment of virtual content to the environment.


Spontaneous remission of acute monocytic leukemia after infection with Clostridium septicum.
Spontaneous remissions of acute myeloid leukemia (AML) have been reported in association with infection. Here, we report a case of spontaneous remission of AML in a 47-year-old Saudi Arabian male patient who presented with a few weeks history of recurrent abdominal pain, vomiting and fever. He was diagnosed with acute monocytic leukemia (AML, FAB M5b) and a perforated bowel. He also had Clostridium septicum bacteremia and thus chemotherapy was deferred. He received supportive therapy and intravenous antibiotics. Six weeks later, he achieved spontaneous and complete remission lasting for about 4 months. The remission and relapse were documented by bone marrow examination. Similarly, previous reports of spontaneous remission of AML were short lived and were followed by relapse and progression.


Human monoclonal anti-idiotypic antibody to the tumour-associated antibody 791T/36.
A human monoclonal antibody, 105AD7, was produced by fusion of a mouse/human heteromyeloma cell line with lymphocytes from a patient previously injected with mouse monoclonal antibody 791T/36 for tumour immunoscintigraphy. The 105AD7 hybridoma has been in continuous culture for more than 12 months, producing a human monoclonal IgG1 which binds to 791T/36 (IgG2b) and its IgG2a class switch variant, but not a range of other monoclonal mouse immunoglobulins. In quantitative flow cytometric assays, 105AD7 was shown to block the binding of fluorescein-labelled 791T/36 to its target gp72 antigen at the surface of tumour cells, but not the binding of 228, an anti-carcinoembryonic antigen (CEA) monoclonal antibody to CEA. Tests with purified 105AD7 antibody demonstrated a stoichiometric high-affinity interaction between 105AD7 and 791T/36. Thus 105AD7 is a human anti-idiotypic antibody which binds at or very close to the binding site of 791T/36, and as such is a candidate for anti-idiotypic immunization of cancer patients.


Effect of the thiol group on experimental gold-induced autoimmunity.
Brown Norway rats injected with aurothiopropanolsulfonate sodium salt develop systemic autoimmunity. The aim of this study was to assess the influence of the sulfur-containing group in this experimental model of gold-induced autoimmunity. It was shown that the sulfur-containing group does not induce autoimmunity of itself, but potentiates the immunotoxic effects of gold.


Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model.
OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.


Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication.
Defects in mitochondrial oxidative phosphorylation have frequently been associated with Alzheimer's disease (AD), and both inherited and somatic mtDNA mutations have been reported in certain AD cases. To determine whether mtDNA mutations contribute more generally to the etiology of AD, we have investigated the sequence of the mtDNA control region (CR) from AD brains for possible disease-causing mutations. Sixty-five percent of the AD brains harbored the T414G mutation, whereas this mutation was absent from all controls. Moreover, cloning and sequencing of the mtDNA CR from patient and control brains revealed that all AD brains had an average 63% increase in heteroplasmic mtDNA CR mutations and that AD brains from patients 80 years and older had a 130% increase in heteroplasmic CR mutations. In addition, these mutations preferentially altered known mtDNA regulatory elements. Certain AD brains harbored the disease-specific CR mutations T414C and T477C, and several AD brains between 74 and 83 years of age harbored the CR mutations T477C, T146C, and T195C, at levels up to 70-80% heteroplasmy. AD patient brains also had an average 50% reduction in the mtDNA L-strand ND6 transcript and in the mtDNA/nuclear DNA ratio. Because reduced ND6 mRNA and mtDNA copy numbers would reduce brain oxidative phosphorylation, these CR mutations could account for some of the mitochondrial defects observed in AD.


Oral rehydration solution to prevent nephrotoxicity of amphotericin B.
Treatment with amphotericin B deoxycholate (AB) is associated with dose-related nephrotoxicity. We conducted an open and randomized trial to evaluate the efficacy of an oral rehydration solution (ORS) to prevent nephrotoxicity of AB, compared with an intravenous saline solution (SS). Adult patients with mucosal leishmaniasis in whom AB was indicated received either three liters or ORS or one liter of SS. Renal function tests were performed at baseline and during treatment. Forty-eight patients were included (ORS = 25, SS = 23). No difference was observed in serum creatinine, creatinine clearance, serum urea, and serum sodium values during treatment, but serum potassium values were lower in the SS group than in the ORS group (P < 0.03). Treatment was more temporarily discontinued in the SS group than in the ORS group (7 patients versus 1 patient, P = 0.02). We conclude that ORS is comparable to SS in preventing glomerular damage of AB, but more effective in preventing hypokalemia.


Between-Frequency Topographical and Dynamic High-Order Functional Connectivity for Driving Drowsiness Assessment.
Previous studies exploring driving drowsiness utilized spectral power and functional connectivity without considering between-frequency and more complex synchronizations. To complement such lacks, we explored inter-regional synchronizations based on the topographical and dynamic properties between frequency bands using high-order functional connectivity (HOFC) and envelope correlation. We proposed the dynamic interactions of HOFC, associated-HOFC, and a global metric measuring the aggregated effect of the functional connectivity. The EEG dataset was collected from 30 healthy subjects, undergoing two driving sessions. The two-session setting was employed for evaluating the metric reliability across sessions. Based on the results, we observed reliably significant metric changes, mainly involving the alpha band. In HOFCθα , HOFCαβ , associated- HOFCθα , and associated- HOFCαβ , the connection-level metrics in frontal-central, central-central, and central-parietal/occipital areas were significantly increased, indicating a dominance in the central region. Similar results were also obtained in the HOFCθαβ and aHOFCθαβ . For dynamic-low-order-FC and dynamic-HOFC, the global metrics revealed a reliably significant increment in the alpha, theta-alpha, and alpha-beta bands. Modularity indexes of associated- HOFCα and associated- HOFCθα also exhibited reliably significant differences. This paper demonstrated that within-band and between-frequency topographical and dynamic FC can provide complementary information to the traditional individual-band LOFC for assessing driving drowsiness.


Normal limits of pediatric Frank lead electrocardiograms. Differences in data obtained in 4th or 5th intercostal spaces.
Frank lead electrocardiograms (VCGs) were recorded from 970 young subjects in order to establish normal limits for pediatric VCGs. In 245 children and 231 adolescents, the thoracic electrodes were located at the levels of the 4th and of the 5th intercostal space with subjects in supine position. Pairwise comparisons of 211 linear and angular parameters were made, using the 4th interspace as the reference. In children, there were 155 parameters with statistically significant differences and 56 parameters without significant differences between levels 4 and 5. In adolescents, corresponding figures were 158 parameters with significant differences and 53 without. Results for selected measurements showed an increase of the amplitude of Q and R waves in leads X and Y, a decrease of Q and R waves in lead Z and an increase of maximal spatial and planar QRS vectors, with the QRS loop being more anteriorly oriented by shifting the electrodes from level 4 to level 5. The mean differences in amplitude and orientation were generally small and of little practical value. However, the percentile distribution of the differences indicated that substantial changes in either direction can occur in some subjects. Thus, quantitative analysis of the pediatric Frank VCGs can be critically affected by modification of electrode placement. It is suggested that normal limits should be determined for each recording level and that criteria for analysis should be applied only to VCGs recorded at the same specified level.


Restriction fragment length polymorphisms in bovine major histocompatibility complex class II beta-chain genes using bovine exon-containing hybridization probes.
Restriction fragment length polymorphisms (RFLPs) have been identified in the bovine MHC class II region using five hybridization probes constructed from two bovine genomic clones. Four probes were constructed from a bovine DR beta-like gene, BoLA-DRB2. These included a probe containing the complete beta 1 exon (R2-beta 1), a probe containing the last 129 base pairs of the beta 2 exon (R2-beta 2), a probe containing intron immediately 5' of the beta 2 exon (R2-5' beta 2), and a probe containing the complete transmembrane exon (R2-TM). A fifth probe was constructed from a novel bovine beta-chain gene, BoLA-DIB, and contained the entire TM exon (I1-TM). R2-beta 1 defined very little polymorphism. R2-beta 2 hybridized to several fragments but one or two fragments hybridized much stronger on all Southern blots and it was presumed these corresponded to BoLA-DRB2 fragments. By using R2-5' beta 2 as a probe, these BoLA-DRB2 fragments were confirmed: 6.4 and 2.7-kb Eco RI alleles, 1.7- and 1.5-kb Pvu II alleles, 5.9-, 5.4-, 3.7- and 1.9-kb TaqI alleles, and a non-polymorphic 22.5-kb BamHI fragment. I1-TM identified three alleles with TaqI. To investigate the linkage between the RFLP alleles, 166 offspring of five sires were tested. Complete linkage was found for all RFLPs identified with the BoLA-DRB2 probes. However, the RFLP patterns of 13 calves out of 58 indicated recombination between BoLA-DRB2 and BoLA-DIB.


Factors influencing the production of wheezes during expiratory maneuvers in normal subjects.
We recorded wheezes, pleural pressure, plethysmographic lung volumes and mouth flow rates in 6 healthy subjects during maximal expiratory maneuvers breathing air and a mixture of 80% He-20% O2 (He) before and after methacholine inhalation. During expiratory flow maneuvers a critical pleural pressure was needed before wheezes occurred. All but one wheeze occurred in the last two thirds of vital capacity during forced exhalation where flow limitation existed. At a flow rate of 2 liters/s, the critical pleural pressure breathing air was 21 +/- 5.8 cm H2O (mean +/- SD), whereas that of breathing He was higher: 32 +/- 7.8 cm H2O (p less than 0.02). In addition the wheezes occurred at lower lung volumes (associated with small airway diameters) when He was breathed instead of air. This was seen both before (p less than 0.02) and after (p less than 0.01) methacholine. These findings suggested that for a given flow rate a lighter gas such as He had to acquire a higher linear velocity so that the convective acceleration was sufficient to produce wheezes. This was achieved by either an increase in the driving critical pleural pressure or narrowing of bronchi by a larger compressing pleural pressure or smaller lung volumes.


Replica model for an unusual directed polymer in 1+1 dimensions and prediction of the extremal parameter of gapped sequence alignment statistics.
Sequence alignment is one of the most important bioinformatics tools for modern molecular biology. The statistical characterization of gapped alignment scores has been a long-standing problem in sequence alignment research. In this paper, we provide a self-contained exposition of sequence alignment, a short review about how this problem is related to the directed polymer problem in statistical physics, and some analytical results that can be used for predicting alignment score statistics. Basically, we present two classes of solutions for the gapped alignment statistics by explicitly calculating the evolution of the few-replica partition function in 1+1 dimensions. We have obtained the conditions under which the more important extremal parameter lambda, characterizing the alignment score statistics, becomes predictable.


Gap junction communication between chromaffin cells: the hidden face of adrenal stimulus-secretion coupling.
From birth to death, catecholamine secretion undergoes continuous adjustments, allowing the organism to adapt to homeostasis changes. To cope with these stressful conditions, the neuroendocrine cells of the adrenal medulla play an immediate and crucial role. Chromaffin cell-driven catecholamine release is chiefly controlled by a neurogenic command that arises from the sympathetic nervous system, which releases acetylcholine at the splanchnic nerve terminal-chromaffin cell synapses. In addition to receiving several synaptic inputs individually, chromaffin cells are coupled by gap junctions. This raises interesting questions about the usefulness and the role of the gap junctional coupling within the chromaffin tissue, considering that secretory function is efficiently completed by the neurogenic pathway. The findings that gap junctions contribute to catecholamine secretion, both ex vivo and in vivo, provide some early answers, but their involvement in other cellular functions still remains unexplored. This review summarizes the molecular and physiological evidence that gap junctions can act either as an accelerator or a brake of stimulus-secretion coupling and discusses this functional plasticity in the context of specific needs in circulating catecholamine levels. It introduces the concept of gap junctions as sympathetic activity sensors and guardians of the functional integrity of the chromaffin tissue.


Local Health Integration Networks: Build on their purpose.
This article provides a high-level overview on the creation of Local Health Integration Networks (LHINs) and illustrates the complexities involved in their implementation. To understand regional structures such as LHINs, one must understand the context in which design and execution takes place. The article ends with a commentary on how Ontario is performing post-LHINs and discusses next steps.


[Usefulness of lactate dehydrogenase concentration in thoracic and abdominal fluid of dogs].
The aims of this study were to investigate the usefulness of LDH measurement in effusions in dogs to classify the fluid as exudate or transudate and to classify the fluid based on the pathophysiological mechanism. In thoracic (n = 107) and abdominal (n = 199) fluid of dogs cell count, protein and LDH concentrations were measured. The fluid was retrospectively categorized into exudate (group A), protein-poor (B) or protein-rich transudate (C) as well as based on pathophysiology into the following five groups (group 1 - 5): hemorrhagic, chylous, inflammatory, oncotic and congestive. In thoracic and abdominal fluid LDH concentrations were significantly higher in group A compared to group B and C. There was a significant difference of LDH concentration between the groups 1 to 5 in both thoracic and abdominal fluid, however there was a large overlap between the five groups. While fluid LDH measurement in dogs is helpful to distinguish exudate from transudate it is only of little help to elucidate the pathophysiological cause.


A user-centred approach to developing bWell, a mobile app for arm and shoulder exercises after breast cancer treatment.
The study aim was to develop a mobile application (app) supported by user preferences to optimise self-management of arm and shoulder exercises for upper-limb dysfunction (ULD) after breast cancer treatment. Focus groups with breast cancer patients were held to identify user needs and requirements. Behaviour change techniques were explored by researchers and discussed during the focus groups. Concepts for content were identified by thematic analysis. A rapid review was conducted to inform the exercise programme. Preliminary testing was carried out to obtain user feedback from breast cancer patients who used the app for 8 weeks post surgery. Breast cancer patients' experiences with ULD and exercise advice and routines varied widely. They identified and prioritised several app features: tailored information, video demonstrations of the exercises, push notifications, and tracking and progress features. An evidence-based programme was developed with a physiotherapist with progressive exercises for passive and active mobilisation, stretching and strengthening. The exercise demonstration videos were filmed with a breast cancer patient. Early user testing demonstrated ease of use, and clear and motivating app content. bWell, a novel app for arm and shoulder exercises, was developed by breast cancer patients, health care professionals and academics. Further research is warranted to confirm its clinical effectiveness. Mobile health has great potential to provide patients with information specific to their needs. bWell is a promising way to support breast cancer patients with exercise routines after treatment and may improve future self-management of clinical care.


Validating Small Molecule Chemical Probes for Biological Discovery.
Small molecule chemical probes are valuable tools for interrogating protein biological functions and relevance as a therapeutic target. Rigorous validation of chemical probe parameters such as cellular potency and selectivity is critical to unequivocally linking biological and phenotypic data resulting from treatment with a chemical probe to the function of a specific target protein. A variety of modern technologies are available to evaluate cellular potency and selectivity, target engagement, and functional response biomarkers of chemical probe compounds. Here, we review these technologies and the rationales behind using them for the characterization and validation of chemical probes. In addition, large-scale phenotypic characterization of chemical probes through chemical genetic screening is increasingly leading to a wealth of information on the cellular pharmacology and disease involvement of potential therapeutic targets. Extensive compound validation approaches and integration of phenotypic information will lay foundations for further use of chemical probes in biological discovery.


Inhibition of sodium-glucose cotransporter 2 to slow the progression of chronic kidney disease.
Chronic kidney disease (CKD) is a major public health problem, increasing the risk of cardiovascular events and death and potentially leading to kidney failure. Novel drugs that slow the progression of this non-communicable disease are therefore urgently needed. Initially developed as glucose-lowering drugs, inhibitors of the sodium-glucose cotransporter 2 (SGLT2) drastically reduce the overall mortality and cardiovascular events and slow the progression of CKD. Kidney protection conferred by SGLT2 inhibitors is independent from the presence of diabetes, observed on top of renin-angiotensin system inhibition and consistent across a wide range of categories of glomerular filtration rate and albuminuria. The mechanisms through which SGLT2 inhibitors improve kidney outcomes are likely multifactorial. Inhibition of SGLT2 in the kidney proximal tubule results in natriuresis and glucosuria, with beneficial effects on metabolic control, blood pressure and body weight. In addition, SGLT2 inhibitors also improve intraglomerular hemodynamics, podocyte integrity, cell metabolism, and erythropoiesis and reduce hypoxia, oxidative stress, sympathetic nervous activity, inflammation and fibrosis. The major impact of SGLT2 inhibitors on kidney outcomes, along with the excellent safety profile of this new class of drugs, open novel avenues for the treatment of CKD in patients with and without diabetes.


Dal81 Regulates Expression of Arginine Metabolism Genes in Candida parapsilosis.
Fungi can use a wide variety of nitrogen sources. In the absence of preferred sources such as ammonium, glutamate, and glutamine, secondary sources, including most other amino acids, are used. Expression of the nitrogen utilization pathways is very strongly controlled at the transcriptional level. Here, we investigated the regulation of nitrogen utilization in the pathogenic yeast Candida parapsilosis. We found that the functions of many regulators are conserved with respect to Saccharomyces cerevisiae and other fungi. For example, the core GATA activators GAT1 and GLN3 have a conserved role in nitrogen catabolite repression (NCR). There is one ortholog of GZF3 and DAL80, which represses expression of genes in preferred nitrogen sources. The regulators PUT3 and UGA3 are required for metabolism of proline and γ-aminobutyric acid (GABA), respectively. However, the role of the Dal81 transcription factor is distinctly different. In S. cerevisiae, Dal81 is a positive regulator of acquisition of nitrogen from GABA, allantoin, urea, and leucine, and it is required for maximal induction of expression of the relevant pathway genes. In C. parapsilosis, induction of GABA genes is independent of Dal81, and deleting DAL81 has no effect on acquisition of nitrogen from GABA or allantoin. Instead, Dal81 represses arginine synthesis during growth under preferred nitrogen conditions. IMPORTANCE Utilization of nitrogen by fungi is controlled by nitrogen catabolite repression (NCR). Expression of many genes is switched off during growth on nonpreferred nitrogen sources. Gene expression is regulated through a combination of activation and repression. Nitrogen regulation has been studied best in the model yeast Saccharomyces cerevisiae. We found that although many nitrogen regulators have a conserved function in Saccharomyces species, some do not. The Dal81 transcriptional regulator has distinctly different functions in S. cerevisiae and C. parapsilosis. In the former, it regulates utilization of nitrogen from GABA and allantoin, whereas in the latter, it regulates expression of arginine synthesis genes. Our findings make an important contribution to our understanding of nitrogen regulation in a human-pathogenic fungus.


Development of a new risk model for predicting cardiovascular events among hemodialysis patients: Population-based hemodialysis patients from the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS).
Cardiovascular (CV) events are the primary cause of death and becoming bedridden among hemodialysis (HD) patients. The Framingham risk score (FRS) is useful for predicting incidence of CV events in the general population, but is considerd to be unsuitable for the prediction of the incidence of CV events in HD patients, given their characteristics due to atypical relationships between conventional risk factors and outcomes. We therefore aimed to develop a new prognostic prediction model for prevention and early detection of CV events among hemodialysis patients. We enrolled 3,601 maintenance HD patients based on their data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS), phases 3 and 4. We longitudinaly assessed the association between several potential candidate predictors and composite CV events in the year after study initiation. Potential candidate predictors included the component factors of FRS and other HD-specific risk factors. We used multivariable logistic regression with backward stepwise selection to develop our new prediction model and generated a calibration plot. Additinially, we performed bootstrapping to assess the internal validity. We observed 328 composite CV events during 1-year follow-up. The final prediction model contained six variables: age, diabetes status, history of CV events, dialysis time per session, and serum phosphorus and albumin levels. The new model showed significantly better discrimination than the FRS, in both men (c-statistics: 0.76 for new model, 0.64 for FRS) and women (c-statistics: 0.77 for new model, 0.60 for FRS). Additionally, we confirmed the consistency between the observed results and predicted results using the calibration plot. Further, we found similar discrimination and calibration to the derivation model in the bootstrapping cohort. We developed a new risk model consisting of only six predictors. Our new model predicted CV events more accurately than the FRS.