Genitourinary Tuberculosis: A Brief Manual for Urologists on Diagnosis and Treatment from the European Association of Urology Urological Infections Panel.
Although tuberculosis (TB) ranks among the most frequent infectious diseases worldwide, one of its extrapulmonary (EP) manifestations, genitourinary (GU) TB, is often underestimated by urologists, particularly in areas such as Europe where TB is not endemic. The aim of this review is to give urologists a concise overview of GUTB as a supplement to the more comprehensive European Association of Urology 2023 update on urological infections guidelines. EPTB can develop in 16% of TB cases. GUTB accounts for 4.6% of EPTB and is often asymptomatic or nonspecific, so it can be confused with other urogenital diseases. GUTB can be highly destructive, leading to failure of urogenital organs. Diagnosis is via microbiological, molecular, and histological testing for urine, genital secretions, or genitourinary tissue, supported by imaging. A 6-mo combinational medical regimen is the first-line treatment for GUTB. However, surgical interventions are also frequently required for the treatment of GUTB complications. Therefore, it is important to keep GUTB in mind for differential diagnosis. PATIENT SUMMARY: We reviewed scientific studies on the occurrence, diagnosis, and treatment of tuberculosis in the genitourinary tract. Our aim is to raise awareness among urologists from countries where this disease does not occur frequently, as urogenital tuberculosis can occur without any symptoms or with unspecific symptoms that can be confused with other diseases.


[Primary study on pathogenesis of Campylobacter jejuni enteritis].
The invasiveness and heat-labile enterotoxin of 11 human strains of C. jejuni were detected in NIH mice inoculated with the C. jejuni strains; the methods of plate immunological hemolysin test and SPA-coagglutination test were employed. Ten strains of the bacteria invaded the intestine; 7 strains (45.46%) were positive in SPA-coagglutination test; and 4 (36.36%) produced enterotoxin. C. jejuni in Chengdu area possess multiple pathogenicity, e.g invasiveness and heat-labile enterotoxin, but we did not find definitive correlations between the clinical manifestation and resource of strains.


Silica and silicates in femoral lymph nodes of barefooted people in Ethiopia with special reference to elephantiasis of the lower legs.
Electron microscopy of femoral lymph nodes of barefooted Ethiopians show the presence of numerous particles of colloid-size and electron-density in the lysosomes of the macrophages in the gland. On diffraction analysis, the particles are found to be amorphous. Elemental microanalysis of the X-ray spectrum indicate the predominance of Si, Al and Fe. In elephantiasics some particles contain silicon alone, presumably silica. The distribution of the Al/Si ratios of the particles in subjects with elephantiasis of the lower legs show a difference from that of non-elephantiasics which is statistically "highly significant" at p less than 0.001. The importance of this as a possible aetiological factor in the disease is discussed. The hypothesis that the disease is discussed. The hypothesis that the disease is a silicosis of the peripheral lymphatics of the lower limbs is supported by the present study.


Investigation of the use of luminescent markers as gunshot residue indicators.
The addition of luminescent markers into ammunition cartridges is an appealing proposal to achieve a greater individual identification of the ammunition. The lanthanide elements present in these luminescent materials act as characteristic chemical markers that, also, offer the great benefit of making gunshot residues (GSR) collection easier. Although the use of luminescent markers offers numerous advantages, and can be a reliable future option in the cartridge ammunition market, little or nothing is known about the interaction of the marker with the ammunition compounds after the shot. For the forensic laboratories, it is of utmost importance to anticipate the commercialization of tagged luminescent ammunition by knowing the type of particles produced after the discharge. That is, to investigate if markers merge with GSR to form single particles or, on the contrary, they form individual particles that travel separately from the GSR particles. In this work, conventional ammunition cartridges tagged with two types of luminescent markers were shot. Then, the particles produced were visualized under UV light on the floor, clothing targets and the shooter. The luminescent particles spread over the floor determined the shooter position and the bullet trajectory. The illumination of the shot targets allows the visualization of the GSR patterns only using a portable UV lamp, avoiding the use of colorimetric test. The GSR particles were collected and subjected to SEM-EDX and Raman spectroscopy analysis to get information about their inorganic and organic composition. The results indicated that part of the marker and the GSR merge and travel together. With this, particles composed by the marker and propellant organic compounds can be identified by Raman spectroscopy, and the unequivocal identification of the GSR and the marker can be achieved by SEM-EDX. Consequently, the luminescent particles detected under UV light improve the evidence collection and offer information about the GSR and the marker. Additionally, this study support the use of luminescent ammunition to study, for example, the transfer or persistence of GSR.


Impact of alcohol-based hand sanitizers, antibiotic consumption, and other measures on detection rates of antibiotic-resistant bacteria in rural Japanese hospitals.
There are limited data available on the relationship between multidrug-resistant bacteria and infection control activities in small to medium-sized hospitals. Therefore, we collected data on the use of alcohol-based hand sanitizers (ABHSs), personal protective equipment, antibiotics, and the levels of detectable bacteria between April 2014 and March 2015 in 11 Japanese hospitals. Average total antibiotic consumption was 100 defined daily doses per 1000 patient-days (PD), and average use of ABHSs, masks, plastic aprons, and gloves was 5 L per 1000 PD, and 1, 2, and 26 pieces per 1 PD, respectively. Average numbers of isolated (isolation rate) Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing bacteria, and multidrug-resistant Pseudomonas aeruginosa (MDRP) were 107 (8% of total bacterial tests performed), 51 (4%), and 4 (0.3%), respectively. Multivariate analyses of ABHS and tazobactam/piperacillin consumption showed a significant negative association with the MRSA isolation rate (adjusted R2 = 0.87). These findings suggest that hand hygiene is more important than antibiotic consumption in small to medium-sized hospitals.


[Which are the true incidence rates of primary hematological disorders acquired in our population?].
To define demographic and epidemiological characteristics of primary haematological disorders (PMHD) in patients referred to a haematology department in 1,240 beds general hospital. 01/94-12/94. We have performed a study in patients older than 14, to determine the age adjusted incidence rates of PHD in the assigned population: 439,279 inh (M: 210,139; F: 229,140), with a negative-vegetative growth (-1.39/10(3) inh/y). A total of 1,242 new cases was received, 302 of them were diagnosed of PHD. Epidemiological method: incidence rates (IR), age and sex adjusted incidence rates (AIR), truncated standardized incidence rates (TSIR) and confidence interval (CI) were calculated. Normal distribution, descriptive and frequency distribution analysis were performed along with chi 2 test. Demographic data: mean age (+/- SD): 63.54 y +/- 15.81; range 19-92. M/F: 177/125, males mean age 62.85 +/- 16.29, females: 64.52 +/- 15.11. The PHD distribution was: MGUS 84 cases; NHL 57; MDS 33; CLL 26; CMPD 26; MM 21; HD 14; AL 11; ITP 10; CML 9; AIHA 5; hypoplastic anaemia 3; and cryoglobulinaemia 3. AIR (cases/10(5) inhab/y): Consulting rate 261.79. The PHD incidence rate was 31.00 (M: 38.01; F: 25.51). In patients under 60 y the AIR of PMDH was 31.31 (M: 36.42, F: 26.25), and in those older than 60 y the AIR was increasing, with 178.86 (M: 247.21, F: 128.52). The AIR for subtypes was: MGUS, 8.01 (M: 3.56, F: 1.93); CLL 2.28 (M: 2.69, F: 1.95); CMPD 3.17 (M: 2.83, F: 3.51); MM 1.92 (M: 2.43, F: 1.49); HD 2.27 (M: 3.54, F: 1.04); AL 1.41 (M: 1.54, F: 1.30); ITP 1.15 (M: 1.20, F: 1.12); CML 1.09 (M: 1.19, F: 1.01); AIHA 0.61 (M: 0.55, F: 0.69); hypoplastic anaemia 0.24 (M: 0.19, F: 0.30); cryoglobulinaemia 0.34 (M: 0.55, F: 0.14). The elderly have increased incidence of PHD. The AIR is higher in males and in older than 60 y, unless for CMPD. Most frequent PHD were MGUS and NHL.


Oxisuran: influence on allograft rejection and graft versus host reactivity in chickens and mice.
Oxisuran, a reported differential suppressant of cell-mediated immunity in several mammalian species, was evaluated for its capacity to prolong allograft survival and reduce graft versus host reactivity in chickens. In addition, the capacity of oxisuran to modulate cell-mediated immunity in mice was reappraised. In the chicken, the administration of 50, 100, or 1000 mg of oxisuran/kg body weight did not significantly prolong allograft survival. Furthermore, graft versus host (GVH) reactivity was not significantly diminished following treatment with 50 or 100 mg of oxisuran/kg body weight; however, GVH reactivity was significantly suppressed after administration of a high dose, 1000 mg of oxisuran/kg body weight. In mice, 100 mg of oxisuran/kg body weight slightly prolonged the survival of H-2a allografts on H-2d recipients, but it did not significantly alter GVH reactivity. Thus, the capacity of oxisuran to significantly suppress cell-mediated immune functions can be questioned at least in the species studied.


Aging.
The normal adult brain undergoes considerable morphological changes with aging. Studying these changes is paramount to differentiate normal age-related brain variations from the effects of neurodegenerative diseases affecting brain structure in the elderly. Considerable progress has been made in this research area during the past few decades, given the availability of noninvasive imaging tools such as magnetic resonance (MR). In recent years image acquisition devices, computer technology and software development have also advanced, allowing sophisticated methods for analyzing brain images, at both the macro-and microstructural level. In this article we will review studies assessing the effect of aging on global and regional gray and white matter volume using advanced MR techniques.


Antipsychotic medications and extreme weight gain in two health systems.
We conducted this study to investigate the rate of clinically important, extreme weight gain (EWG; ≥7% body weight gain) among all second generation antipsychotic (SGA) users in two large health care systems in the United States. Retrospective observational cohort study. We used electronic medical record databases of two health systems to identify adults aged 18-79 years who from 1 January 2004 to 31 December 2011 had initiated a SGA medication. All patients had to have a minimum of two weight measures in the medical record: (1) one or more weights in the 180-day pre-treatment (baseline) period; and (2) one or more weights in the first year after initiating SGA treatment. We found that EWG occurred in 7.7-17.0% of SGA users. At one year, the average weight gain was nearly 10kg among SGA users who experienced EWG. Olanzapine was the SGA most commonly associated with EWG with a rate of 17.0 per 100 users [95% confidence interval (CI): 14.2-20.5], while ziprasidone was least commonly associated with EWG (7.7 per 100 users; 95% CI: 4.6-13.0). We found that clinically-important weight gain was common after the initiation of SGA treatment, and the EWG phenotype was easily identifiable within electronic medical records. There was significant heterogeneity in the rate of EWG across SGA medications. Weight gains of this magnitude are likely to have adverse health consequences and there is a significant unmet opportunity for physicians to identify these events and mitigate the harms of SGA use.


Ontogeny of the hypothermic response to centrally administered neurotensin in rats.
Neurotensin (NT), an endogenous tridecapeptide, when given intracisternally (i.c.) elicits significant hypothermia in a variety of mammals. The present study was designed to test the ability of centrally administered NT to induce a hypothermic effect in rats at different ages. Intracisternally administered NT (10 and 30 microgram) produced a marked dose-dependent hypothermia in rats aged 5, 10, 20, 30 and 60 days. This study confirms and extends the previously reported hypothermic effect of centrally administered NT in the rat and documents the responsiveness of young animals to the peptide.


[Is a strategy of bio-socio-ethic necessary?].
The aim of this paper is to assess the need for a common ethics strategy shared by 2 of the cornerstones of human welfare: the healthcare and social services sectors. An observational cross-sectional descriptive study was performed by surveying social services and healthcare professionals. A purposive sampling technique was used. The questionnaire consisted of 10 questions about ethical conflicts in professional practice and respondents' views on a proposed shared approach to bioethics and ethics in social intervention. 124 professionals completed the questionnaire, 56% of the health sector and 44% of the social services sector. About 90% professionals surveyed had had to make difficult ethical decisions in their work and would welcome a common approach to ethics in the social services and healthcare sectors. 75% said that conflicts are occurring more frequently in both sectors simultaneously and that they were resolved preferably individually and independently. The survey respondents believe that a common approach to tackling ethical conflicts in professional practice is required. Nevertheless, it is still rare for ethics committees to intervene in the conflict resolution process and for decision-making support and evaluation tools to be used.


Thermal interaction between animal and microclimate: a comprehensive model.
An equation based on heat transfer theory is developed to predict the rate of heat loss from a homeothermic vertebrate to the environment, specified by the air temperature, humidity, windspeed and radiation receipt. The analysis incorporates the animal's thermoregulatory responses--sweating ability, vasomotor action, and regulation of body-core temperature, metabolic and respiratory rate. The loss of heat and water vapour from cattle is used as an illustration, and particular attention is given to their heat balance in hot environments. The predicted rates of heat loss from cattle indoors at various air temperatures and humidities are consistent with experiments. Outdoors, intercepted solar radiation can reduce substantially heat loss through the body tissue when the air temperature is low. In contrast, at high air temperatures the heat dissipation may not be sensitive to the radiation load, although body-core temperature is. Increased rates of air movement can aggravate strain at low air temperatures, but mitigate strain in a hot environment.


Preoperative diagnosis and prediction of microvascular invasion in hepatocellularcarcinoma by ultrasound elastography.
To assess the values of two elastography techniques combined with serological examination and clinical features in preoperative diagnosis of microvascular invasion in HCC patients. A total of 74 patients with single Hepatocellular carcinoma (HCC) were included in this study. Shear wave measurement and real-time tissue elastography were used to evaluate the hardness of tumor-adjacent tissues and tumor tissues, as well as the strain rate ratio per lesion before surgery. According to the pathological results, the ultrasound parameters and clinical laboratory indicators related to microvascular invasion were analyzed, and the effectiveness of each parameter in predicting the occurrence of microvascular invasion was compared. 33/74 patients exhibited microvascular invasion. Univariate analysis showed that the hardness of tumor-adjacent tissues (P = 0.003), elastic strain rate ratio (P = 0.032), maximum tumor diameter (P < 0.001), and alpha-fetoprotein (AFP) level (P = 0.007) was significantly different in the patients with and without microvascular invasion. The binary logistic regression analysis showed that the maximum tumor diameter (P = 0.001) was an independent risk factor for predicting microvascular invasion, while the hardness of tumor-adjacent tissues (P = 0.028) was a protective factor. The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of the hardness of tumor-adjacent tissues, the maximum diameter of the tumor, and the predictive model Logit(P) in predicting the occurrence of MVI was 0.718, 0.775 and 0.806, respectively. The hardness of tumor-adjacent tissues, maximum tumor diameter, and the preoperative prediction model predict the occurrence of MVI in HCC patients.


Geochemical signature of urbanisation in Blue Mountains Upland Swamps.
Urbanisation leaves a geochemical signature on the environment, as weathering of urban materials such as concrete contributes to elevated levels of major ions including calcium, bicarbonate and potassium. However, there is limited research that addresses the ecological consequences of this signature on the biotic community. Blue Mountains Upland Swamps (BMUS), an endangered ecological community with high conservation values, are vulnerable to urban degradation. Chemical properties of water, sediment and foliage from native and exotic species were assessed within two urbanised and two naturally vegetated swamp catchments. Water in urban swamps exhibited elevated pH and electrical conductivity. Non-urban swamps were sodium and chloride dominated, with higher calcium and bicarbonate in urban swamps. Water from urban swamps also exhibited 32 times higher levels of strontium. Calcium concentrations were elevated by 14 times in urban swamp sediment. Foliage from urban catchments exhibited six times greater potassium, and three times higher calcium and bicarbonate compared to foliage in non-urban catchments. Calcium, bicarbonate, potassium and strontium were key parameters that were enriched in the urbanised swamps. However, the ecological implications of these findings for urban wetland communities, including BMUS, remain unclear. Interestingly, the chemical signature of water did not fully represent the signatures of sediment and foliage, highlighting the need to further explore sources and forms of major ions within these ecosystems, particularly in sediment. In an increasingly urban world, enhancing knowledge of drivers of change in endangered ecosystems such as BMUS is crucial to promote conservation and guide the development of sustainable management practices.


Successful prenatal molecular diagnosis of carbamyl-phosphate synthetase I deficiency in two at-risk pregnancies.
We report the two first prenatal diagnoses in an Italian family with a proband affected by neonatal carbamyl-phosphate synthetase I deficiency in which molecular analysis identified V457G and Q810R amino acid substitutions. We performed a prenatal diagnosis on genomic DNA isolated from chorionic villus and amniotic fluid samples collected at 13 weeks of gestation. In the first pregnancy, the fetus was compound heterozygous for the mutations and termination of pregnancy was elected. The genetic lesions were also confirmed on genomic DNA isolated from the fetus's liver and skin fibroblasts. A few months later, we performed a second prenatal diagnosis in this family. The second fetus was heterozygous for the wild-type alleles. The pregnancy was continued and a girl was born at 41 weeks of gestation. We have confirmed the wild-type state on the baby's DNA.


A forced expiration end-segment flow rate to improve diagnosis of reversible bronchial obstruction: a spirographic examination.
An inhalatory bronchodilatory test was performed in two groups of 130 healthy and 89 asthmatics comparable in age, height and weight. All were males aged about 20 years. The bronchodilatory response was assessed by the percent increase after bronchodilation of FEV1, MEF200-1200, MMEF25-75 MEF50-75 (E50-75) and MEF75-90--at last three flow rate percent increases measured before and after bronchodilation at the same level of control FVC. It was found that only MEF75-90, measured as described, could probably significantly improve the diagnostic value of a bronchodilatory test if used in cases in which the FEV1 percent increase remains within the normal range.


Methionine loading does not enhance the predictive value of homocysteine serum testing for all-cause mortality or major adverse cardiac events.
Hyperhomocysteinaemia is independently associated with atherosclerotic disease. Methionine loading could improve the predictive value of hyperhomocysteinaemia by detecting mild disturbances in enzyme activity. The aims of this study were to determine the beneficial effect of methionine loading on the predictive value of homocysteine testing for long-term mortality and major adverse cardiac events (MACE). In an observational study, 1122 patients with suspected or known vascular disease, underwent homocysteine testing, which was measured fasting and again 6 h after methionine loading. Hyperhomocysteinaemia was defined as a fasting level > or =15 micromol/L and post-methionine loading level > or =45 micromol/L or an increase of > or =30 micromol/L above fasting levels. Primary end-points were death and MACE. Multivariate Cox regression analysis was used, adjusting for all cardiac risk factors. During follow up (mean 8.9 +/- 3.4 years), 98 patients died (8.7%), 86 had a MACE (7.7%), 579 patients had normal tests, 134 patients had only fasting hyperhomocysteinaemia, 226 only post-methionine hyperhomocysteinaemia and 183 patients had both. In multivariate analysis, overall survival and MACE-free survival were significantly worse for those with fasting hyperhomocysteinaemia, with hazard ratios of 1.86 (95% confidence interval (CI) 1.20-2.87) and 2.24 (95%CI 1.41-3.53), respectively. The addition of hyperhomocysteinaemia after methionine loading did not significantly increase the risk of death or MACE, with hazard ratios of 0.97 (95%CI 0.52-1.81) and 0.89 (95%CI 0.47-1.69), respectively. The presence of post-methionine hyperhomocysteinaemia did not significantly alter risk of death or MACE in patients with normal or increased fasting homocysteine levels, respectively. In conclusion, methionine loading does not improve the predictive value of homocysteine testing with regard to long-term mortality or MACE.


Combinatorial-Hierarchical DNA Library Design Using the TeselaGen DESIGN Module with j5.
Modern DNA assembly techniques are known for their potential to link multiple large DNA fragments together into even larger constructs in single pot reactions that are easier to automate and work more reliably than traditional cloning methods. The simplicity of the chemistry is in contrast to the increased work needed to design optimal reactions that maximize DNA fragment reuse, minimize cost, and organize thousands of potential chemical reactions. Here we examine available DNA assembly methods and describe through example, the construction of a complex but not atypical combinatorial and hierarchical library using protocols that are generated automatically with the assistance of modern synthetic biology software.


Recent progress in the design of DNA vaccines against tuberculosis.
Current tuberculosis (TB) vaccines have some disadvantages and many efforts have been undertaken to produce effective TB vaccines. As a result of their advantages, DNA vaccines are promising future vaccine candidates. This review focuses on the design and delivery of novel DNA-based vaccines against TB.


Renal consequences of parenteral nutrition.
Parenteral nutrition (PN) can be described as the "Intravenous administration of nutrients necessary to sustain life in those who would otherwise have died or suffered serious disease". PN is indicated in children who cannot be fully fed by the oral or intestinal route, usually as a result of intestinal failure. Intradialytic parenteral nutrition (IDPN) is rarely indicated in children on dialysis and does not confer a benefit over enteral supplements in the compliant patient with adequate intestinal function. Renal and metabolic consequences of PN are potentially life-threatening and include disorders of glucose homeostasis, acid-base and fluid and electrolyte disturbances, nephrolithiasis, impaired renal function and metabolic bone disease. Many of these complications are avoidable. Adequate clinical and biochemical assessment and monitoring of children receiving PN by a multidisciplinary nutrition support team is recommended to mitigate against the risks of these complications.


Low serum cobalamin levels in a population study of 70- and 75-year-old subjects. Gastrointestinal causes and hematological effects.
We examined causes and hematological consequences of low serum cobalamin (vitamin B12) concentration in two representative population samples of 70-year-old (N = 293) and 75-year-old subjects (N = 486). Subjects with values below 130 pmol/liter (4.8% and 5.6%, respectively) were investigated with Schilling test, upper gastrointestinal endoscopy, determination of serum gastrin and group I pepsinogens, and bone marrow examination. Gastrointestinal abnormalities of etiologic significance were found in 26 of the 32 examined subjects: atrophy of the gastric body mucosa (N = 16, with pernicious anemia in six), partial gastrectomy (N = 6), and intestinal malabsorption (N = 4). Megaloblastic hematopoiesis was found in 10 individuals, four of whom had macrocytic anemia. Our results indicate that low serum cobalamin concentration in the elderly is usually a consequence of disease rather than of high age per se and that gastric mucosal atrophy is a major etiologic factor.


Pre-TCRalpha and TCRalpha are not interchangeable partners of TCRbeta during T lymphocyte development.
In contrast with the alphabeta T cell receptor (TCR), the pre-TCR spontaneously segregates to membrane rafts from where it signals in a cell-autonomous fashion. The disparate behaviors of these two receptors may stem either from differences inherent to the distinct developmental stages during which they are expressed, or from features intrinsic and unique to the receptor components themselves. Here, we express TCRalpha precisely at the pre-TCR checkpoint, at levels resembling those of endogenous pre-TCRalpha (pTalpha), and in the absence of endogenous pTalpha. Both in isolation and more dramatically when in competition with pTalpha, TCRalpha induced defective proliferation, survival, and differentiation of alphabeta T lymphocyte precursors, as well as impaired commitment to the alphabeta T lymphocyte lineage. Substitution of TCRalpha transmembrane and cytoplasmic domains with those of pTalpha generated a hybrid molecule possessing enhanced competitive abilities. We conclude that features intrinsic to the pre-TCR, which are absent in TCRalpha, are essential for its unique function.


New horizons in the imaging of perianal Crohn's disease: transperineal ultrasonography.
perianal disease, most commonly manifest as fistula or abscess formation, affects up to 40% of patients with crohn's disease. perianal crohn's disease is disabling, associated with poor outcomes, and represents a therapeutic challenge for physicians. correct diagnosis and classification of perianal disease is the first crucial step for appropriate multidisciplinary management. Areas covered: A literature search was performed of the PubMed database using the terms 'transperineal ultrasonography', 'transperineal ultrasound', 'perianal disease', 'perianal fistula', 'perianal abscess', 'magnetic resonance', 'endoanal ultrasonography', 'endoscopic ultrasound' in combination with 'Crohn's disease'. A comprehensive review of the relative advantages and disadvantages of the various methods of evaluation of perianal Crohn's disease is provided. A particular focus is placed on transperineal ultrasonography, including historical and technical factors, advantages and limitations, and its current role in practice. An algorithm for integration of transperineal ultrasound into the management of perianal Crohn's disease into clinical practice is proposed, along with future areas research. Expert commentary: Transperineal ultrasound is a simple, safe, cheap and reliable imaging technique for evaluation of perianal Crohn's disease, which should be used more frequently in clinical practice.


Urinary concentration and tissue messenger RNA expression of monocyte chemoattractant protein-1 as an indicator of the degree of hydronephrotic atrophy in partial ureteral obstruction.
To find a potential prognostic marker of the induction of hydronephrotic atrophy in congenital hydronephrosis we investigated whether the messenger (m)RNA expression and urinary concentration of monocyte chemoattractant protein-1 (MCP-1) correlated with the degree of partial ureteral obstruction, and subsequent hydronephrotic atrophy and interstitial fibrosis. We created left partial ureteral obstruction in 96 juvenile Wistar rats and complete ureteral obstruction in 18, while 16 underwent sham operation. Depending on excretion of contrast medium into the renal pelvis after 3 days we defined 2 degrees of hydronephrosis. Renal mRNA expression of MCP-1, and renal pelvic and bladder urinary concentrations of MCP-1 were measured after 1, 2 and 3 weeks, and compared with the degree of hydronephrotic atrophy. Grade 1 partial ureteral obstruction resulted in mild histological changes. Grade 2 partial and complete obstruction resulted in significant hydronephrotic atrophy. MCP-1 mRNA expression in the kidney remained unchanged in grade 1 partial obstruction but was moderately increased in grade 2 partial obstruction and clearly over expressed in complete ureteral obstruction. The renal pelvic urinary concentration of MCP-1 was not higher in rats with grade 1 partial obstruction than in sham operated animals but it was significantly increased in those with grade 2 partial and complete obstruction. mRNA expression and the urinary concentration of MCP-1 correlate with the degree of obstruction and subsequent renal damage in hydronephrosis. They may serve as prognostic markers in children with congenital hydronephrosis.


Endothelial damage during myocardial preservation and storage.
Preservation and storage techniques represent two major issues in routine cardiac surgery and heart transplantation. Historically, these methods were conceived to prevent ischemic injury to myocardium after cardiac arrest during heart operations. Evidence shows that endothelium plays a critical role in the maintenance of normal heart function after cardiac operation, mainly by controlling the coronary circulation. Methods for preservation and storage, developed initially to protect cardiomyocyte function, may be deleterious for vascular endothelium and compromise myocardial protection. In this review article the present knowledge about endothelial injury secondary to preservation and storage techniques is discussed.


Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade.
(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.


Density and ultrastructure of mast cells in lung vessels of aging rats exposed to and recovering from chronic hypoxia.
A decrease in pulmonary vascular responsiveness in aging animals during exposure to chronic hypoxia has been previously reported; however, morphological documentation is lacking. Lungs from young (3-5 months) and aging (12-14 months) Sprague-Dawley rats, exposed to and recovering from chronic hypoxia, were morphometrically analyzed at the light-microscopic level for changes in perivascular mast cells, and at the electron-microscopic level for cellular alterations. While young rat lungs showed proliferation of mast cells around elastic and muscular pulmonary arteries and arterioles, perivascular mast cell density in lungs of aging rats was significantly greater than in young rat lungs. At the ultrastructural level, perivascular mast cells in aging hypoxic rats showed numerous profiles of cellular extensions that contained remnants of discharged secretory vesicles. The results suggest that increased proliferation of perivascular mast cells as well as increased secretory activity of vasoactive substances in aging animals might represent a humoral determinant of the hyporesponsiveness of pulmonary vessels that occurs with increasing age during chronic hypoxia.


Demonstration of intracytoplasmic IgE in circulating lymphocytes of allergic individuals.
Cells containing intracytoplasmic IgE (IC IgE) were demonstrated in the peripheral blood mononuclear cells of atopic individuals by means of indirect immunofluorescence, employing mouse monoclonal anti-human IgE antibody. IC IgE-positive cells are low-density B cells as shown by centrifugation on discontinuous bovine serum albumin density gradient and by their reactivity with B1 monoclonal antibody specific to B lymphocytes, respectively. Further characterization of these cells by means of a rosette assay employing anti-Ig-coupled bovine erythrocytes indicated that these cells were surface IgE (sIgE) positive and sIgM negative. The data strongly suggest that activated IgE B cells are circulating in the blood of allergic individuals.


SMARTtest: A Smartphone App to Facilitate HIV and Syphilis Self- and Partner-Testing, Interpretation of Results, and Linkage to Care.
Acceptability of rapid HIV self-testing is high but potential users remain concerned about correct use, interpretation of test results, and linkage to care. This article describes user preferences for a smartphone app to mitigate these challenges and how these were integrated into the SMARTtest app to support self- and partner-testing using the INSTI Multiplex®. Sixty men and transgender women who have sex with men self-tested for HIV and syphilis while guided by a prototype app that provided a video, pictorial step-by-step instructions, and sample test results presented textually ("positive," "negative"). Subsequently, participants provided feedback on revisions and additional app content. Participants recommended offering different user modes (self, partner, both), and retaining the video, step-by-step instructions, and textual test results. They strongly favored the ability to save and send test results to sexual partners or providers. These features were integrated into the SMARTtest app to facilitate HIV/syphilis self- and partner-testing, HIV/syphilis status awareness and disclosure, and linkage to care.


Three-dimensional comparison of interventional MR radiofrequency ablation images with tissue response.
Solid tumors are being treated using radiofrequency (RF) ablation under interventional magnetic resonance imaging (MRI) guidance. We are investigating the ability of MRI to monitor ablation treatments by comparing MR images of thermal lesions to histologically assayed tissue damage. An open MRI system was used to guide an ablation electrode into five rabbit thigh muscles and acquire post-ablation MR image volumes. We developed a methodology using a 3D computer registration to make spatial correlations. After MR and histology images were registered with an accuracy of 1.32+/-0.39 mm (mean+/-SD), a boundary of necrosis identified in the histology was compared with the outer boundary of the hyperintense region in MR images. For 14 T2-weighted MR images, the absolute distance between boundaries was 0.96+/-0.34 mm (mean+/-SD). Since the small discrepancy between boundaries is comparable to our registration accuracy, the boundaries may match exactly. Similar correlations to histology were obtained with a deformable model segmentation method. This is good evidence that MR thermal lesion images can be used during RF ablation treatments to accurately localize the zone of necrosis at the lesion margin.


Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.
Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.


The natural history of adults with Rubinstein-Taybi syndrome: a families-reported experience.
The existing knowledge about morbidity in adults with Rubinstein-Taybi syndrome (RTS) is limited and detailed data on their natural history and response to management are needed for optimal care in later life. We formed an international, multidisciplinary working group that developed an accessible questionnaire including key issues about adults with RTS and disseminated this to all known RTS support groups via social media. We report the observations from a cohort of 87 adult individuals of whom 43 had a molecularly confirmed diagnosis. The adult natural history of RTS is defined by prevalent behavioural/psychiatric problems (83%), gastrointestinal problems (73%) that are represented mainly by constipation; and sleep problems (62%) that manifest in a consistent pattern of sleep apnoea, difficulty staying asleep and an increased need for sleep. Furthermore, over than half of the RTS individuals (65%) had skin and adnexa-related problems. Half of the individuals receive multidisciplinary follow-up and required surgery at least once, and most frequently more than once, during adulthood. Our data confirm that adults with RTS enjoy both social and occupational possibilities, show a variegated experience of everyday life but experience a significant morbidity and ongoing medical issues which do not appear to be as coordinated and multidisciplinary managed as in paediatric patients. We highlight the need for optimal care in a multidisciplinary setting including the pivotal role of specialists for adult care.


Evolving techniques and perspectives in lung transplantation.
Lung transplantation is currently a suitable option for patients with end-stage lung disease. Since the early 1980s the surgical technique and immunosuppressive protocols have been progressively modified to improve results and favor long-term survival. The original heart-lung transplantation under cardiopulmonary bypass is now rarely performed and single or bilateral lung transplantation is the procedure of choice. Bilateral transplantation is performed with two single lung transplants performed in sequence. Extracorporeal support is rarely employed and in most cases it is instituted through the femoral approach. Also, the surgical approach has been modified and the original clam shell incision has been replaced by two small anterior thoracotomies. The use of marginal donors has been increasingly proposed to enlarge the number of organs potentially available for transplantation. Immunosuppressive protocols have evolved to patient-specific regimens that can be quickly modified if required by the clinical status. Induction is now more aggressive and also rescue protocols for obliterative bronchiolitis can contribute to improved outcomes. Overall, lung transplantation is now performed with encouraging long-term results.


Mitochondrial transport of protoporphyrinogen IX in erythroid cells.
Comment on: Yien Y, et al. TMEM14C is required for erythroid mitochondrial heme metabolism. J. Clin. Invest. 2014; 124:4294-4304.


Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier.
Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined expression, regulation, and functions of ABCG1, ABCG4, and apoM in primary porcine brain capillary endothelial cells (pBCEC). RT Q-PCR analyses and immunoblotting revealed that in addition to ABCA1 and scavenger receptor, class B, type I (SR-BI), pBCEC express high levels of ABCG1, which was up-regulated by LXR activation. Immunofluorescent staining, site-specific biotinylation and immunoprecipitation revealed that ABCG1 is localized both to early and late endosomes and on apical and basolateral plasma membranes. Using siRNA interference to silence ABCG1 (by 50%) reduced HDL-mediated [3H]-cholesterol efflux (by 50%) but did not reduce [3H]-24(S)-hydroxycholesterol efflux. In addition to apoA-I, pBCEC express and secrete apoM mainly to the basolateral (brain) compartment. HDL enhanced expression and secretion of apoM by pBCEC, apoM-enriched HDL promoted cellular cholesterol efflux more efficiently than apoM-free HDL, while apoM-silencing diminished cellular cholesterol release. We suggest that ABCG1 and apoM are centrally involved in regulation of cholesterol metabolism/turnover at the BBB.


The near-mid-IR HOMO-LUMO gap in amide linked porphyrin-rhodamine dyads.
Novel amide linked porphyrin-rhodamine dyads yield utmost intense red-shifted electronic transitions beyond the near-infrared region.


Isolation and characterization of two minor fractions of alpha 1-antitrypsin by high-performance liquid chromatographic chromatofocusing.
alpha 1-Antitrypsin is a glycoprotein that separates into five electrophoretic fractions, viz. M2, M4, M6, M7 and M8. Con A-Sepharose separates the protein into three fractions according to the branching degree of the three oligosaccharide chains. The Con A affinity is identical for M4 and M7 and for M6 and M8. Within each pair the proteins were isolated by rapid chromatofocusing. The M7 and M8 have the same carbohydrate structure as the major M4 and M6 respectively, but have lost the first five N-terminal amino acids (Glu-Asp-Pro-Glu-Gly) as compared to the majority of the protein.


Mucocele of the appendix: an unusual finding at exploration for right-sided inguinal pain.
A case of mucocele of the appendix, uncovered during an abdominal exploration on a tentative diagnosis of incipient inguinal hernia, is reported. The small mucocele is unlikely to have been responsible for the recorded symptoms and signs.


Accessory lateral rectus muscle in a patient with congenital third-nerve palsy.
To report a case of accessory lateral rectus muscle in a patient with congenital third-nerve palsy. Observational case report. An 18-year-old boy with left exodeviation, ptosis, pupil dilation, and limited adduction, supraduction, and infraduction of his left eye. Left lateral rectus muscle recession and medial rectus muscle resection were done. An orbital computed tomographic (CT) scan was obtained. Intraoperatively, an accessory muscle was found under the lateral rectus muscle. Postoperatively, the orbital CT scan showed accessory lateral rectus muscle located in the medial side of the lateral rectus muscle. Accessory lateral rectus muscle was demonstrated in a patient with congenital third-nerve palsy using lateral rectus muscle surgery and an orbital CT scan.


Somatometric measurements, and clinical chemistry and hematology parameters in Tibetan macaque (Macaca thibetana).
Limited physiological data for Tibetan macaques are available at present. This study will provide more rationale for evaluating this species. Thirty-seven Tibetan macaques (15 males and 22 females) were used in this study. Somatometric measurements, clinical chemistry and hematology parameters, insulin, and C-peptide were analyzed. Females had higher values of waist and waist hip ratio (WHR) than males in somatometric measurements. There were no significant differences between the two genders in hematology. Significant differences between males and females were only found for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in biochemistry testing. In addition, females had higher fasting insulin and C-peptide than males. There was a strongly positive correlation between age and some somatometric parameters. These physiological data will provide veterinarians and researchers with baseline values to evaluate experimental results using Tibetan macaques.


Targeted dosing for susceptible heteroresistant subpopulations may improve rational dosage regimen prediction for colistin in broiler chickens.
The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total population) mixed with an initial minor subpopulation of less susceptible bacteria (S2). Herein, we report the 1-compartment population pharmacokinetics (PK) of colistin in chicken intestine (jejunum and ileum) and combined it with a previously established pharmacodynamic (PD) model of HR in E. coli. We then computed probabilities of target attainment (PTA) with a pharmacodynamic target (AUC24h/MIC) that achieves 50% of the maximal kill of bacterial populations (considering inoculums of pure S1, S2 or HR mixture of S1 + S2). For an MIC of 1 mg/L, PTA > 95% was achieved with the registered dose (75,000 IU/kg BW/day in drinking water) for the HR mixture of S1 + S2 E. coli, whether they harboured mcr or not. For an MIC of 2 mg/L (ECOFF), we predicted PTA > 90% against the dominant susceptible sub-population (S1) with this clinical dose given (i) over 24 h for mcr-negative isolates or (ii) over 6 h for mcr-positive isolates (pulse dosing). Colistin clinical breakpoint S ≤ 2 mg/L (EUCAST rules) should be confirmed clinically.


Effects of feedback caudate nucleus stimulation on spontaneous fast amygdaloid spindles and drive.
Experiments with single and repetitive stimulation of the head of the caudate nucleus (4-10 V, 0.3 msec) triggered by occurrence of fast amygdaloid spindles (35 c/s microV, 0.5 sec) were performed in six animals with chronically implanted cerebral electrodes. In conjunction with the anterior cortical recruiting response the stimulation increased the incidence of amygdaloid fast spindles and decreased the incidence of hippocampal theta activity and of searching eye movements. The associative training failed, however, to significantly modify in the background EEG, the mean incidence of the fast amygdaloid spindles or the rate of the sensorimotor rhythm of 12-18 c/s. Its only effect (after long repetition) was a displacement to the right of the regression line of the incidence of the two rhythms and a slight alteration in the slope. The possibility of activating the caudate nucleus inhibitory effects through the amygdala during internal inhibition phenomena is discussed.


Simultaneous 3D acquisition of 1 H MRF and 23 Na MRI.
To develop a 3D MR technique to simultaneously acquire proton multiparametric maps (T1 , T2 , and proton density) and sodium density weighted images over the whole brain. We implemented a 3D stack-of-stars MR pulse sequence which consists of interleaved proton (1 H) and sodium (23 Na) excitations, tailored slice encoding gradients that can encode the same slice for both nuclei, and simultaneous readout with different radial trajectories (1 H, full-radial; 23 Na, center-out radial). The receive chain of our 7T scanner was modified to enable simultaneous acquisition of 1 H and 23 Na signal. A heuristically optimized flip angle train was implemented for proton MR fingerprinting (MRF). The SNR and the accuracy of proton T1 and T2 were evaluated in phantoms. Finally, in vivo application of the method was demonstrated in five healthy subjects. The SNR for the simultaneous measurement was almost identical to that for the single-nucleus measurements (<2% change). The proton T1 and T2 maps remained similar to the results from a reference 2D MRF technique (normalized RMS error in T1 ≈ 4.2% and T2 ≈ 11.3%). Measurements in healthy subjects corroborated these results and demonstrated the feasibility of our method for in vivo application. The in vivo T1 values measured using our method were lower than the results measured by other conventional techniques. With the 3D simultaneous implementation, we were able to acquire sodium and proton density weighted images in addition to proton T1 , T2 , and B1+ from 1 H MRF that covers the whole brain volume within 21 min.


Cortical afferents to the prefrontal cortex of the cat: a study with the horseradish peroxidase technique.
Following horseradish peroxidase (HRP) injections into different areas within the prefrontal cortex (PFC) of the cat, labeled neurons were found in the cingulate and insular cortex. These results demonstrate that the cat's prefrontal cortex is reached directly from these cortical regions, and that the observed cortical projections are similar to those detected in the monkey's prefrontal cortex.


Association between individual differences in self-reported emotional resilience and the affective perception of neutral faces.
Resilience, i.e., the ability to cope with stress and adversity, relies heavily on judging adaptively complex situations. Judging facial emotions is a complex process of daily living that is important for evaluating the affective context of uncertain situations, which could be related to the individual's level of resilience. We used a novel experimental paradigm to test the hypothesis that highly resilient individuals show a judgment bias towards positive emotions. 65 non-treatment seeking subjects completed a forced emotional choice task when presented with neutral faces and faces morphed to display a range of emotional intensities across sadness, fear, and happiness. Overall, neutral faces were judged more often to be sad or fearful than happy. Furthermore, high compared to low resilient individuals showed a bias towards happiness, particularly when judging neutral faces. This is a cross-sectional study with a non-clinical sample. These results support the hypothesis that resilient individuals show a bias towards positive emotions when faced with uncertain emotional expressions. This capacity may contribute to their ability to better cope with certain types of difficult situations, especially those that are interpersonal in nature.


Regulatory considerations for the potential development and application of metal cleanup values.
This article addresses the regulatory issues associated with the application of recent data to support Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) requirements in Europe and the use of metal-specific parameters by other countries to generate remediation values for metals in soil. The purposes of this article are to: 1) present approaches and advances developed over the last decade in Europe for the REACH regulation and proposed in Australia by the National Environment Protection Council, 2) review current US and Canadian regulatory practices on ecological soil cleanup values, and 3) evaluate the application of new scientific approaches, methods, and soil criteria development processes used in other countries.


New insights in the prevalence of scoliosis and musculoskeletal asymmetries in adolescents with esophageal atresia.
Increased risk of scoliosis and musculoskeletal abnormalities in adolescents with esophageal atresia (EA) is reported, but the impact of these abnormalities on physical fitness and motor skills are not known. Scoliosis was assessed radiographically and shoulder and chest abnormalities by a standardized protocol. Physical fitness was evaluated with Grippit, Six-minute walk test, and International Physical Activity Questionnaire and motor skills by Motor Assessment Battery for Children. Sixty-seven EA adolescents median 16 (13-20) years participated. The prevalence of significant scoliosis (≥ 20º) was 12% (8/67) whereas 22% (15/67) had mild scoliosis (10-19º). Vertebral anomalies occurred in 18/67 (27%), eight of them (44%) had scoliosis. The majority of adolescents (15/23) with scoliosis did not have vertebral anomalies. Musculoskeletal abnormalities were detected in 22-78%. Balance problems occurred three times more frequently than expected (44% vs. 15%, p = 0.004). Submaximal exercise capacity was significantly reduced compared to reference values (p < 0.001). Scoliosis ≥ 20º was related to reduced physical activity (p = 0.008), and musculoskeletal abnormalities to reduced physical activity and impaired motor skills (p = 0.042 and p < 0.038, respectively). Significant scoliosis was diagnosed in 12% of the EA adolescents and related to reduced physical activity. Musculoskeletal abnormalities identified in more than half of the patients, were related to reduced physical activity and impaired motor skills, and exercise capacity was significantly below reference group. EA patients with and without vertebral anomalies need health-promoting guidance to prevent impaired motor skills and consequences of reduced physical activity. Prognostic Study, Level II.


[Studies on metabolites from marine microorganism Aspergillus terreus collected from nature reserve region of mangrove].
To search for new antitumor active lead compounds from marine microorganism. A marine strain, Aspergillus terreus, was cultured and up-scaled in artificial seawater media, from which the metabolites were isolated and elucidated by using modern spectroscopy techniques. Twelve compounds were isolated from mycelia and fermentation broth of A. terreus. Compounds 1-4 were steroids, compounds 5-8 were organic acids and esters, compound 9 was an alkaloid, compound 10 was an isocoumarin, compound 11 was ceramide, compound 12 was propenyl cyclic pentanediol.


Automatically explaining machine learning prediction results: a demonstration on type 2 diabetes risk prediction.
Predictive modeling is a key component of solutions to many healthcare problems. Among all predictive modeling approaches, machine learning methods often achieve the highest prediction accuracy, but suffer from a long-standing open problem precluding their widespread use in healthcare. Most machine learning models give no explanation for their prediction results, whereas interpretability is essential for a predictive model to be adopted in typical healthcare settings. This paper presents the first complete method for automatically explaining results for any machine learning predictive model without degrading accuracy. We did a computer coding implementation of the method. Using the electronic medical record data set from the Practice Fusion diabetes classification competition containing patient records from all 50 states in the United States, we demonstrated the method on predicting type 2 diabetes diagnosis within the next year. For the champion machine learning model of the competition, our method explained prediction results for 87.4 % of patients who were correctly predicted by the model to have type 2 diabetes diagnosis within the next year. Our demonstration showed the feasibility of automatically explaining results for any machine learning predictive model without degrading accuracy.


Association between elevated blood glucose and outcome in acute heart failure: results from an international observational cohort.
The aim of this analysis was to assess the association between elevated blood glucose level and mortality in acute heart failure (AHF). Elevated blood glucose has been reported to be prognostically meaningful in patients with cardiac diagnoses, such as coronary artery disease. The short-term prognostic impact of hyperglycemia in AHF is unknown, however. In a multinational cohort of AHF, we examined the ability of blood glucose concentrations at presentation to predict all-cause mortality by 30 days. Fully adjusted models for prognosis included a previous diagnosis of diabetes mellitus as a covariate. A total of 6,212 subjects with AHF (mean age, 72 years; 52.5% male) were studied; the median blood glucose concentration on arrival at the hospital was 7.5 mmol/l (135 mg/dl), and 41% had a previous diagnosis of diabetes mellitus (DM). After 30 days, 618 patients (10%) had died. Compared with survivors, decedents had significantly higher median blood glucose concentrations (8.9 mmol/l vs. 7.4 mmol/l; p < 0.0001). In the fully adjusted model, an elevated blood glucose level was an independent predictor of 30-day mortality in AHF (odds ratio: 2.19; 95% confidence interval: 1.69 to 2.83; p < 0.001). The risk associated with an elevated blood glucose level appeared consistent across all subgroups of patients, including patients with preserved (hazard ratio: 5.41; 95% confidence interval: 2.44 to 12.0; p < 0.0001) and impaired systolic function (hazard ratio: 2.37; 95% confidence interval: 1.57 to 3.59; p < 0.0001). Furthermore, in reclassification analyses, elevated blood glucose added significant prognostic information to clinical parameters alone (4.4% net reclassification improvement; p = 0.01). Among patients with AHF, blood glucose concentrations at presentation are powerfully prognostic for 30-day mortality, independent of a diagnosis of diabetes mellitus or other clinical variables. Because blood glucose is easily modifiable, it may represent a valid target for therapeutic intervention.


The relationships between leptin and inflammatory cytokines in women with pre-eclampsia.
To compare maternal serum leptin concentration in women with pre-eclampsia and women with normal pregnancy, and to evaluate the relationships between leptin and several inflammatory cytokines. Prospective clinical study. University Hospital of Puerto Real, Cadiz, Spain. Twenty-seven women with pre-eclampsia and 25 normotensive pregnant women. Maternal serum levels of TNF-alpha, TGF-beta1, interleukin 6, and leptin were measured using a commercially available immunoassay. Maternal serum levels of leptin and its relationship to levels of TNF-alpha, TGF-beta1 and interleukin 6. Maternal serum leptin levels were higher in women with pre-eclampsia, but this difference was of borderline statistical significance (median 15.9 ng/mL; interquartile range (5.4-31.9) vs 30.5 ng/mL (13.9-64) (P = 0.05). The concentration of maternal serum leptin was correlated with pre-gestational and gestational body mass index (r = 0.45, P = 0.03; r = 0.44, P = 0.04), TNF-alpha concentration (r = 0.57, P = 0.002) and interleukin-6 level (r = 0.46, P = 0.02) in women with normal pregnancy. In women with pre-eclampsia, only a significant correlation between maternal serum leptin level and TNF-alpha concentration (0.47, P = 0.01) was found. The level of maternal serum leptin is increased and correlates positively with the level of TNF-alpha in women with pre-eclampsia. In women with a normal pregnancy leptin levels not only correlate with TNF-alpha, but also with IL-6 and body mass index.


Is it justified to assess the resectability of pancreatic cancer combined with biological and conditional factors?
This study aimed to investigate the biological and conditional resectability criteria for pancreatic ductal adenocarcinoma (PDAC), as proposed by the International Association of Pancreatology (IAP), as well as to identify the role of biological and conditional factors in assessing the resectability of PDAC. The clinical data of PDAC patients who underwent upfront open/laparoscopic pancreaticoduodenectomy (PD/LPD) or distal pancreatectomy (DP/LDP) at our hospital between January 2013 to June 2019 were retrospectively analyzed. Patients who were diagnosed with anatomically resectable PDAC, as defined by National Comprehensive Cancer Network (NCCN) guideline of PDAC guideline Version 1.2020, were enrolled. Based on IAP-criteria, these patients were divided into two groups, including IAP-resectable (IAP-R) and IAP Borderline Resectable (IAP-BR). Clinical characteristics and outcomes were compared between the two groups. In order to identify independent biological and conditional predictors of recurrence-free survival (RFS) and overall survival (OS) of enrolled patients, an analysis was performed through the use of a Cox proportional-hazard model. Overall, 97 patients were included in this study. Among them, 38 patients were IAP-R and 59 patients were IAP-BR. Compared to the IAP-R group, the IAP-BR group had a higher early recurrence rate (62.7% vs. 42.1%; P=0.047), and the median RFS (9.2 vs. 18.3 months, P<0.01) and OS (19.1 vs. 30.6 months, P<0.05) were also significantly worse. Preoperative CA19-9 serum levels that exceeded 500 U/mL and/or an imaging diagnosis of regional lymph nodes metastasis were independently associated with OS and RFS of anatomically resectable PDAC. The prognosis of patients with PDAC that undergo resection can be predicted more accurately by assessing the resectability of pancreatic cancer combined with anatomical and biological factors according to IAP criteria. Whether conditional factors should be included in the resectability criteria needs to be validated by prospective and large cohorts.


Toxicology digital sources produced and available in the United Kingdom (UK).
This paper looks at toxicology digital sources produced and available in the United Kingdom (UK). It includes products aggregating a number of sources, which may include information from other countries, and for the convenience of the reader and information seeker these have also been described.


Physiology of transport regulation.
The regulation of biological transport is discussed on the basis of studies on sodium transport through amphibian skin. The following types of regulation are briefly considered: 1) Hormonal regulation 2) Regulation of Na entry by apparent or real saturation of entry path by outside Na 3) Regulation of Na transport by changes in resistance to the counter ion (mostly chloride) 4) Role of cellular Na concentration which may act both by controlling the passive entry of Na and by influencing the pumping rate. 5) Dependence of Na entry upon cell volume. It is shown that a moderate osmotic swelling of ouabain-poisoned skins leads to excessive swelling of the whole epithelium when NaCl is present on the outside. This indicates that cell swelling leads to opening of the Na channels, but it also indicates coupling between the different layers of the epithelium.


Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT)
Advantages and disadvantages of postmenopausal oestrogen replacement therapy (ERT) are still not clear. We aimed to analyse the relation between postmenopausal oestrogen replacement therapy (ERT), cardiovascular disease, and cancer. We examined 7944 women born between 1923 and 1930, who participated in a mammography screening for breast cancer, and who were followed up from 1987 to 1995. The follow-up consisted of 53,305 person-years. 988 women were current users and 757 were former users of ERT. Information about hormone use and health events was obtained through biennial questionnaires and recording and linking information from the hospital discharge registers of the region, the national cancer register, the social insurance reimbursement register, and the national death register. We used proportional-hazards models to calculate risk ratios and 95% CIs, adjusted for eight confounding variables. Current ERT was associated with decreased cardiovascular mortality and a decrease in sudden cardiac death. Adjusted risk ratio (RR) for cardiovascular mortality in current users was 0.21 (95% CI 0.08-0.59) and in former users 0.75 (0.41-1.37). Absolute risk per 1000 person-years for deaths from acute myocardial infarction (AMI) was 1.1 in never users, 1.2 in former users, and 0.45 in current users (p=0.197). Corresponding absolute risk for other coronary-artery-disease (CAD) deaths was 1.0, 0.81, and 0 (p=0.009), and for deaths from stroke 1.2, 1.0, and 0.15 (p=0.012). Absolute risk for sudden cardiac death was 1.6 in never users, 1.0 in former users, and 0 in current users (p<0.001). Cardiovascular morbidity was not decreased by ERT: the RR for current use was 1.07 (0.86-1.32) and for former use 1.11 (0.89-1.39). Incidence of cardiovascular disease per 1000 person-years was 24.9 in never users, 23.4 in former users, and 20.9 in current users (p=0.153). Breast-cancer morbidity did not increase with current ERT--the RR was 0.57 (0.27-1.20). Incidence of breast cancer was 1.8, 1.6, and 1.0 in never, former, and current users (p=0.242). Endometrial cancer increased with current ERT--the RR was 5.06 (2.47-10.41). Incidence of endometrial cancer was 0.52 in never users, 0.51 in former users, and 2.1 in current users (p<0.001). Current ERT reduced primarily sudden cardiac death and predicted reduced cardiovascular mortality, but did not reduce morbidity. ERT did not increase the risk of breast cancer, but was associated with increased risk of endometrial cancer.


Natural history of testicular regression syndrome and consequences for clinical management.
Testicular regression syndrome (TRS or 'vanishing testis') is a condition in which a testis is thought to have once existed but has atrophied and disappeared during early development. The natural history of TRS is in completely understood, due to the absence of any prospectively studied cohort of patients. This study aimed to quantify the cardinal features of the disease and correlate these with age. A total of 117 cases of TRS were submitted for histopathological examination. Patient age ranged from birth to 12 years, with a median age of 2 years. The proportion of each histological feature present was analysed according to age, using the chi(2) test. BIRTH RESULTS: The 117 cases accounted for 21% of the testicular/paratesticular specimens examined. Only 12 cases (10%) were found to contain testicular tissue, with no readily identifiable germ cells and in particular no atypical germ cells identified. Features such as haemosiderin-laden macrophages, calcification, the presence of a nodule, vas or epididymis were less prevalent amongst specimens from older boys. This is the largest series studied to date. With only 10% of the removed specimens containing identifiable testicular tissue with no germ cells seen, a negligible risk of future germ-cell cancer on the affected side is implied. If the laparoscopic findings suggest a diagnosis of vanishing testis, we contend that a groin exploration may be no longer indicated.


Isolation and characterization of aldehyde dehydrogenase isozymes from usual and atypical human livers.
Usual human livers contain two major aldehyde dehydrogenase isozymes, cytosolic ALDH1 component and mitochondrial ALDH2 component, while human livers with "atypical" phenotype have only ALDH1 isozyme and are missing ALDH2 isozyme. Approximately 50% of orientals are atypical in respect to ALDH isozymes. We previously demonstrated an existence of enzymatically inactive but immunologically cross-reactive material (CRM) in atypical oriental livers. ALDH1 and ALDH2 isozymes were purified to homogeneity from usual livers, and ALDH1 and CRM were purified from atypical oriental livers. Amino acid compositions of ALDH1 and ALDH2 were similar to, but not identical with, each other. Amino acid compositions of ALDH2 and CRM were identical within analytical errors. Subunit molecular size of ALDH1 estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 56,200 daltons, and that of ALDH2 was 52,600 daltons. The two isozymes did not contain a common subunit. Subunit molecular weight of CRM was identical with that of ALDH2. Double immunodiffusion precipitation revealed that ALDH1 and ALDH2 were immunologically analogous but not identical, and that CRM and ALDH2 were immunologically indistinguishable. These results support the genetic model that CRM is an abnormal defective protein resulting from a mutation of the ALDH2 locus.


Design and implementation of a Pacific intervention to increase uptake of urate-lowering therapy for gout: a study protocol.
Gout is a painful chronic disease which disrupts work and family life and can lead to chronic joint damage. Pacific people in Aotearoa/New Zealand experience significant inequities, with over three times the gout prevalence of the non-Pacific non-Māori populations. Pacific people receive less regular urate-lowering drugs to prevent gout flare-ups, and have nine times the hospitalisation from gout compared with non-Pacific non-Māori people. Rates for Indigenous Māori lie between Pacific and non-Pacific non-Māori. A long-established Collective comprising community members from the Pacific People's Health Advisory Group, clinical staff from the Pacific Practice-Based Research Network, and University of Auckland researchers have identified that improving Pacific urate-lowering therapy use as the research question of prime importance for improved health outcomes of Pacific people in South Auckland. Building on the existing knowledge, this study aims to develop, implement and evaluate a novel innovative intervention to improve the uptake of urate-lowering therapy by Pacific patients with gout. Three-phase mixed methods co-design study using the Fa'afaletui research framework following the STROBE statement. Phase1 is observational times series of prevalence of patients with gout, proportion with urate blood-level monitoring and use of urate-lowering medication over past 5 years. In Phase 2 the Collective will workshop new interventions to address previous uptake barriers, using culturally-appropriate Talanga communications with results synthesised in line with Kakala principles. The designed intervention will be implemented and process and outcome evaluations conducted. Finally, an implementation framework will be produced to facilitate further roll-out. The study aims to enhance health and reduce inequities for Pacific people, contribute to creation of Pacific health knowledge and translation of research findings into Pacific health gains. Potential longer-term impact is a gout-management pathway for use throughout Aotearoa/New Zealand. Māori have similar issues with high gout prevalence and low urate-lowering therapy use hence the intervention is likely to translate to Māori healthcare. The project will contribute to Pacific research capacity and capability-building as well as general upskilling of community and practice members involved in the co-design processes. The Australian New Zealand Clinical Trial Registry is in process, request number 38206, 1-09-2021.


Comparison of diagnostic efficacy by two urine PCA3 scores in prostate cancer patients undergoing repeat biopsies.
Urine prostate cancer gene 3 (PCA3) is significantly elevated in patients with prostate cancer and can be used for the diagnosis of prostate cancer, but its cutoff value is still controversial. We searched the database on urine PCA3 in the diagnosis of prostate cancer, such as Medline, Web of Science, the Cochrane Library and Embase. Meta-analysis was performed using the random effect model and the sensitivity, specificity, diagnostic odds ratio, and area under the ROC curve (SROC) were calculated. Our meta-analysis included nine studies on PCA3 scores in a total of 1721 suspected prostate cancer patients. When urine PCA3 score was 20, we obtained sensitivity of 0.83, specificity of 0.40, diagnostic odds ratio of 3.11, and the area under the SROC curve was 0.6842 (Q value 0.6404). When urine PCA3 score was 35, we found a lower sensitivity of 0.66, a higher specificity of 0.63 and a relatively lower diagnostic odds ratio of 2.84. The area under the SROC curve was 0.6715, which was slightly lower than urine PCA3 score 20. Our meta-analysis suggested that when the PCA3 score cutoff value was 20, the unnecessary puncture was reduced and obtained a higher diagnostic efficacy.


A novel synthetic peptide derivative from lactoferrin exhibiting antimicrobial activity.
A tetrapeptide derivative Boc-L-Lys(Boc)-L-Arg-L-Asp-L-Ser(Bu(t))-OBu(t) (PEP 1261; Boc is butoxycarbonyl, Bu(t) is t-butyl and OBu(t) is t-butyl ester), synthesized by a solution-phase strategy, exhibited antimicrobial activity against a broad spectrum of micro-organisms at an optimal concentration of 500 mug/ml. Whereas the tetrapeptide salt (L-Lys-L-Arg-L-Asp-L-Ser.HCl) was found to be fairly effective against bacterial cultures, it was not effective against fungal cultures. Comparative growth studies showed that PEP 1261 was equally as potent as the conventional antibiotics kanamycin, streptomycin and actidione for the Gram-negative bacteria Escherichia coli, Pseudomonas alcaligenes and the non-filamentous fungus Saccharomyces cerevisiae (baker's yeast), whereas 62 and 88.9% inhibition were observed for Gram-positive organisms such as Staphylococcus aureus and Bacillus thuringiensis respectively. PEP 1261 might exert its antimicrobial activity by permeabilizing the bacterial membrane, and this was confirmed by an increase in beta-galactosidase activity.


Pathology of cerebral metastases.
Important pathologic features of cerebral metastases include the route of spread of tumor cells to the brain, differences among metastases based on location in dura mater, leptomeninges, and brain parenchyma, differences based on primary tumor site, both known and unknown, the means of spread of metastases within the brain, and the brain's reactions to metastases. Immunohistochemistry and electron microscopy are increasingly used in the pathologic evaluation of cerebral metastasis.


High Performance Pd/4H-SiC Epitaxial Schottky Barrier Radiation Detectors for Harsh Environment Applications.
Although many refractory metals have been investigated as the choice of contact metal in 4H-SiC devices, palladium (Pd) as a Schottky barrier contact for 4H-SiC radiation detectors for harsh environment applications has not been investigated adequately. Pd is a refractory metal with high material weight-to-thickness ratio and a work function as high as nickel, one of the conventional metal contacts for high performing 4H-SiC Schottky barrier detectors (SBDs). In this article, Pd/4H-SiC epitaxial SBDs have been demonstrated for the first time as a superior self-biased (0 V applied bias) radiation detector when compared to benchmark Ni/4H-SiC SBDs. The Pd/4H-SiC SBD radiation detectors showed a very high energy resolution of 1.9% and 0.49% under self- and optimized bias, respectively, for 5486 keV alpha particles. The SBDs demonstrated a built-in voltage (Vbi) of 2.03 V and a hole diffusion length (Ld) of 30.8 µm. Such high Vbi and Ld led to an excellent charge collection efficiency of 76% in the self-biased mode. Capacitance mode deep level transient spectroscopy (DLTS) results revealed that the "lifetime-killer" Z1/2 trap centers were present in the 4H-SiC epilayer. Another deep level trap was located at 1.09 eV below the conduction band minimum and resembles the EH5 trap with a concentration of 1.98 × 1011 cm-3 and capture cross-section 1.7 × 10-17 cm-2; however, the detector performance was found to be limited by charge trapping in the Z1/2 center. The results presented in this article revealed the unexplored potential of a wide bandgap semiconductor, SiC, as high-efficiency self-biased radiation detectors. Such high performance self-biased radiation detectors are poised to address the longstanding problem of designing self-powered sensor devices for harsh environment applications e.g., advanced nuclear reactors and deep space missions.


The Diagnosis of Metastatic Axillary Lymph Nodes of Breast Cancer By Diffusion Weighted Imaging: a meta-analysis and systematic review.
The purpose of this meta-analysis was to evaluate the clinical significance of diffusion-weighted imaging in assessing the status of axillary lymph nodes in patients with breast cancer. We searched the PubMed, Cochrane, and EMBASE databases, selected studies by inclusion and exclusion criteria, and assessed the quality of selected studies. We explored the source of heterogeneity; calculated sensitivity, specificity, positive and negative likelihood ratios, and pretest probability. A summary receiver operating characteristic curve was performed. Student's t test was used to compare the different mean apparent diffusion coefficient values of different status lymph nodes. In selected 10 studies, a total of 801 patients and 2305 lymph nodes were included following inclusion criteria. All scores of the quality assessment of the included studies were greater than or equal to 10 points. The sensitivity was 0.89 (95 % CI 0.79-0.95), the specificity was 0.83 (95 % CI 0.71-0.91), the positive and negative likelihood ratios were 3.86 (95 % CI 2.75-5.41) and 0.17 (95 % CI 0.09-0.32), the pretest probabilities were 53 and 54 %, the area under the curve were 0.93 (95 % CI 0.90-0.95), respectively. The mean apparent diffusion coefficient value of metastatic lymph nodes was significantly lower than that of nonmetastatic axillary lymph nodes. Diffusion-weighted imaging is a promising tool to discriminate between metastatic and nonmetastatic axillary lymph nodes. Combined with the mean apparent diffusion coefficient value, it can quantitatively diagnose lymph node metastases. Conducting large-scale, high-quality researches can improve the clinical significance of diffusion-weighted imaging to distinguish metastatic and nonmetastatic axillary lymph nodes in patients with breast cancer and provide the evidence to assess the status of axillary lymph nodes.


Thyromental height test as a new method for prediction of difficult intubation with double lumen tube.
Predicting difficult intubation is of high clinical interest. 237 patients aged ≥18 years were included in the study. Preoperative airway evaluation included: Mallampati test, thyromental distance, sternomental distance and thyromental height test. During direct laryngoscopy Cormack & Lehane classification was graded. We calculated the ROC AUC, sensitivity and specificity for thyromental height test as a primary end point of our study. Only thyromental height test and Cormack-Lehane scale proved significant on occurrence of difficult intubation. The optimal sensitivity and specificity values of thyromental height test were met with a cut off value of 50 mm. With 1 mm increase in thyromental height test, risk of difficult intubation decreased by 7%. Thyromental height test is a simple, easy to perform and non-invasive test to predict difficult intubation in patients scheduled for elective double lumen tube intubation during thoracic surgical procedures. With 1 mm above 50 mm increase in thyromental height test the risk of difficult intubation decreased by 7%. Clinicaltrials.gov Identifier: NCT02988336.


Electrochemical Oxo-Fluorosulfonylation of Alkynes under Air: Facile Access to β-Keto Sulfonyl Fluorides.
Radical fluorosulfonylation is emerging as an appealing approach for the synthesis of sulfonyl fluorides, which have widespread applications in many fields, in particular in the context of chemical biology and drug development. Here, we report the first investigation of FSO2 radical generation under electrochemical conditions, and the establishment of a new and facile approach for the synthesis of β-keto sulfonyl fluorides via oxo-fluorosulfonylation of alkynes with sulfuryl chlorofluoride as the radical precursor and air as the oxidant. This electrochemical protocol is amenable to access two different products (β-keto sulfonyl fluorides or α-chloro-β-keto sulfonyl fluorides) with the same reactants. The β-keto sulfonyl fluoride products can be utilized as useful building blocks in the synthesis of various derivatives and heterocycles, including the first synthesis of an oxathiazole dioxide compound. Furthermore, some β-keto sulfonyl fluorides and derivatives exhibited notably potent activities against Bursaphelenchus xylophilus and Colletotrichum gloeosporioides.


New mutations affecting induced mutagenesis in yeast.
Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4-38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4+ and REV5+ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.


Fractionation of Palliative Radiation Therapy for Bone Metastases in Ontario: Do Practice Guidelines Guide Practice?
To evaluate the effect of a provincial practice guideline on the fractionation of palliative radiation therapy for bone metastases (PRT.B) in Ontario. The present retrospective study used electronic treatment records linked to Ontario's population-based cancer registry. Hierarchical multivariable regression analysis was used to evaluate temporal trends in the use of single fractions (SFs), controlling for patient-related factors associated with the use of SFs. From 1984 to 2012, 43.9% of 161,835 courses of PRT.B were administered as SFs. The percentage of SF courses was greater for older patients (age <50 years, 39.8% vs age >80 years, 52.5%), those with a shorter life expectancy (survival >12 months, 36.9% vs < 1 month, 53.6%), and those who lived farther from a radiation therapy center (<10 km, 42.1% vs > 50 km, 47.3%). The percentage of SFs to spinal fields was lower than that to other skeletal sites (31.5% vs 57.1%). The percentage of SFs varied among the cancer centers (range, 26.0%-67.8%). These differences were all highly significant in the multivariable analysis (P<.0001). In 2004, Cancer Care Ontario released a practice guideline endorsing the use of SFs for uncomplicated bone metastases. The rate of use of SFs increased from 42.3% in the pre-guideline period (1999-2003) to 52.6% in the immediate post-guideline period (2004-2007). However, it subsequently decreased again to 44.0% (2009-2012). These temporal trends were significant after controlling for patient-related factors in the multivariable analysis (P<.0001). Large intercenter variations in the use of SFs persisted after publication of the guideline. The publication of an Ontario practice guideline endorsing the use of SF PRT.B was associated with only a transient increase in the use of SFs in Ontario and did little to reduce intercenter variations in fractionation.


Quality of life in patients with alcohol use disorders admitted to de-addiction centers using WHOQOL-BREF scale-A cross-sectional study.
Alcohol use disorders (AUDs) adversely affect a person's general health and the lives of their family and friends. These disorders are also the most undertreated mental illness with severe implications for public health. Hence, the present study aimed to employ the WHOQOL-BREF to assess the quality of life (QoL) of AUDs patients seeking treatment at de-addiction centers and identify the demographic variables associated with the QoL dimension scores. A cross-sectional study was conducted among alcohol dependents taking treatment in de-addiction centers in Dakshina Kannada District, Karnataka. The WHOQOL-BREF questionnaire was administered to 124 subjects. Multiple regression analysis was carried out to identify the demographic variables associated with the QoL dimension scores. The domain mean scores were between 50 and 60 on the 0 to 100 scale. Age, social class, residential area, marital status, and years of drinking were the demographic variables found to be significantly associated with the dimension scores. Physicians should monitor the effect of alcoholism on QoL, and a multidisciplinary treatment plan with elements from the medical, social, and psychiatric fields should be used. The demographic variables should be considered while managing patients with AUDs.


Changes in sexual identity and substance use during young adulthood.
Sexual identity is dynamic, and changes in identity (e.g., from heterosexual to lesbian, gay, bisexual, or queer [LGBQ+]) are common during young adulthood. It is not well-understood how sexual identity changes may be associated with substance use risk. Two waves of data (baseline: October, 2018-October, 2019; follow-up: May-October, 2020) were used from a prospective cohort of young adults (N = 1896; mean age=21.2). Frequency of past 30-day use and new initiation of five substance use outcomes (alcohol, any tobacco, e-cigarettes, cannabis, illicit drugs) were compared across four groups: consistently heterosexual (N = 1567), consistently LGBQ+ (N = 244), heterosexual to LGBQ+ (N = 65), and LGBQ+ to heterosexual (N = 20). Consistently LGBQ+ (vs. consistently heterosexual) participants reported greater frequency of past 30-day use of alcohol (aOR=1.34, 95% CI=1.04-1.72), any tobacco products (aOR=1.88, CI=1.34-2.63), e-cigarettes (aOR=1.49, CI=1.01-2.19), cannabis (aOR=1.36, CI=1.01-1.84), and illicit drugs (aOR=2.84, CI=1.77-4.56). Heterosexual to LGBQ+ (vs. consistently heterosexual) participants reported greater frequency of past 30-day use of any tobacco products (aOR=1.87, CI=1.06-3.33) and illicit drugs (aOR=2.48, CI=1.10-5.62), and had greater risk of initiating alcohol (aRR=1.82, CI=1.02-3.25) and cannabis use (aRR=2.90, CI=1.81-4.64). LGBQ+ to heterosexual (vs. consistently LGBQ+) participants reported lower frequency of past 30-day use of alcohol (aOR=0.35, CI=0.14-0.88) and any tobacco products (aOR=0.15, CI=0.03-0.80). Identifying as LGBQ+ was associated with increased risk for frequent substance use, and newly adopting an LGBQ+ identity was associated with increased risk for new substance use initiation. Prevention and treatment interventions may need to tailor messaging to young people who have newly adopted an LGBQ+ identity.


Performance of Five Ultrasound Risk Stratification Systems in Selecting Thyroid Nodules for FNA.
Ultrasound (US) risk stratification systems (RSSs) have been developed to reduce the number of unnecessary fine-needle aspiration procedures (FNA) in patients with thyroid nodules. We conducted a systematic review and meta-analysis evaluating the ability of the 5 most common US RSSs for the appropriate selection of thyroid nodules for FNA. This systematic review and meta-analysis was registered on PROSPERO (CRD42019131771). PubMed, CENTRAL, Scopus, and Web of Science were searched until March 2019. Original articles reporting data on the performance of AACE/ACE/AME, ACR TI-RADS, ATA, EU-TIRADS, and K-TIRADS were included. The number of nodules classified as true negative, true positive, false negative, and false positive was extracted. Summary operating points were estimated using a random-effects model. Interobserver agreement was also assessed. Twelve studies evaluating 18 750 thyroid nodules were included. Participants were adult outpatients with thyroid nodules submitted to either FNA or core-needle biopsy or surgery and with available US images. The final diagnosis for malignant nodules was generally based on histology, while cytology was used for benign nodules. Diagnostic odds ratio (DOR) ranged from 2.2 to 4.9. A head-to-head comparison showed a higher relative DOR for ACR-TIRADS versus ATA (P = .002) or K-TIRADS (P = .002), due to a higher relative likelihood ratio for positive results. The present meta-analysis found a higher performance of ACR TI-RADS in selecting thyroid nodules for FNA. However, the comparison across the most common US RSSs was limited by the data available. Further studies are needed to confirm this finding.


Chemoimmunotherapy in patients with extensive-stage small cell lung cancer and a poor performance status.
Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase 3 clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC excluded patients who had an Eastern Cooperative Group (ECOG) performance status (PS) of 2-3. Therefore, data on the efficacy of chemoimmunotherapy in patients with an ECOG PS of 2-3 are limited. A retrospective analysis was performed on patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. The objective of this study was to compare the overall survival (OS), progression-free survival (PFS), and best clinical response to therapy in patients with an ECOG PS of 0-1 vs. patients with an ECOG PS of 2-3 who received chemoimmunotherapy for newly diagnosed ES-SCLC. In total, 82 patients were included in the study. The mean ± standard deviation age was 68.1 ± 8.3 years. Of these, 56 patients were identified with an ECOG PS of 0-1, and 26 patients were identified with an ECOG PS of 2-3. The median PFS was similar regardless of ECOG PS (5.8 months [95% CI, 4.3-6.0 months] in the ECOG PS 0-1 group vs. 4.1 months [95% CI, 3.8-6.9 months] in the ECOG PS 2-3; p = .2994). The median OS was also similar regardless of ECOG PS (10.6 months [95% CI, 8.4-13.4 months] in the ECOG PS 0-1 group vs. 9.3 months [95% CI, 4.9-12.8 months]; p = .2718) in the ECOG PS 2-3 group. The study results demonstrated no significant difference in PFS or OS among the ECOG PS 2-3 and ECOG PS 0-1 groups. Therefore, chemoimmunotherapy should be considered for patients who have ES-SCLC with an ECOG PS of 2-3.


Rhodamine B and 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose (F-GlcNAc) inhibit chondroitin/dermatan and keratan sulphate synthesis by different mechanisms in bovine chondrocytes.
MPS disorders result from a deficiency or absence of glycosaminoglycan (GAG) degrading enzymes leading to an imbalance between the synthesis and degradation of GAGs and their subsequent accumulation in a range of cells. The inhibition of GAG synthesis using small chemical inhibitors has been proposed as a novel therapeutic approach to treatment. Several inhibitors have been shown to decrease heparan sulphate GAG synthesis and in this study we evaluated a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose (F-GlcNAc)) and rhodamine B for their ability to also inhibit the synthesis of chondroitin/dermatan and keratan sulphate GAGs present in bovine cartilage. Both inhibitors decreased GAG synthesis in chondrocyte monolayer culture and in cartilage chip explant culture in a dose dependent manner. Both inhibitors decreased the size of newly synthesised proteoglycans and in the case of F-GlcNAc this was due to a decrease in newly synthesised GAG chain size. Rhodamine B, however, did not affect GAG chain size, while both inhibitors decreased the amount of chondroitin/dermatan and keratan sulphate GAG equally. The expression of genes responsible for the initiation and elongation of chondroitin/dermatan sulphate and keratan sulphate GAGs were downregulated in the presence of rhodamine B but not in the presence of F-GlcNAc. Thus the 2 inhibitors appear to have differing effects on GAG synthesis, with F-GlcNAc inhibiting the epimerisation of UDP-GlcNAc to UDP-GalNAc thus decreasing the availability of monosaccharides for addition to the growing GAG chain, whereas rhodamine B is more likely to reduce the number of GAG chains. Together with previous data these 2 inhibitors are capable of non-specific inhibition of GAG synthesis, reducing the production of chondroitin/dermatan sulphate, keratan sulphate and heparan sulphate GAGs. As such they would be applicable to therapy in a range of MPS disorders.


Mortality study of cancer risk among oil refinery workers.
The mortality experience of 1595 male workers employed in one of the largest Italian refineries in the period from 1949-1982 was examined. From the comparison with national and local death rates, increases in mortality owing to lung and kidney cancers, brain tumors, and leukemias emerged. No definite trends according to duration of exposure and years since first exposure were apparent. The increases regarding cancer of the lung, kidney and brain appeared to be associated with the early period of operations. Analysis by exposure category suggested an association of the increased mortality from leukemias with working in production (observed = 2; expected = 0.61). Kidney cancer mortality was elevated among maintenance workers (obs. = 2; exp. = 0.18). Small numbers prevented firmer conclusions. Workers in the moving department had a significantly increased mortality from all cancers (obs. = 22; exp. = 11.7), and lung cancer (obs. = 11; exp. = 3.6). Confounding by smoking could be excluded as sufficient explanation of the three-fold increase in lung cancer deaths. It was in moving that highest airborne levels of polynuclear aromatic hydrocarbons had been discovered in an independent environmental investigation.