Dynamic Click Hydrogels for Xeno-Free Culture of Induced Pluripotent Stem Cells.
Xeno-free, chemically defined poly(ethylene glycol) (PEG)-based hydrogels are being increasingly used for in vitro culture and differentiation of human induced pluripotent stem cells (hiPSCs). These synthetic matrices provide tunable gelation and adaptable material properties crucial for guiding stem cell fate. Here, sequential norbornene-click chemistries are integrated to form synthetic, dynamically tunable PEG-peptide hydrogels for hiPSCs culture and differentiation. Specifically, hiPSCs are photoencapsulated in thiol-norbornene hydrogels crosslinked by multiarm PEG-norbornene (PEG-NB) and proteaselabile crosslinkers. These matrices are used to evaluate hiPSC growth under the influence of extracellular matrix properties. Tetrazine-norbornene (Tz-NB) click reaction is then employed to dynamically stiffen the cell-laden hydrogels. Fast reactive Tz and its stable derivative methyltetrazine (mTz) are tethered to multiarm PEG, yielding mono-functionalized PEG-Tz, PEG-mTz, and dualfunctionalized PEG-Tz/mTz that react with PEG-NB to form additional crosslinks in the cell-laden hydrogels. The versatility of Tz-NB stiffening is demonstrated with different Tz-modified macromers or by intermittent incubation of PEG-Tz for temporal stiffening. Finally, the Tz-NB-mediated dynamic stiffening is explored for 4D culture and definitive endoderm differentiation of hiPSCs. Overall, this dynamic hydrogel platform affords exquisite controls of hydrogel crosslinking for serving as a xeno-free and dynamic stem cell niche.


Vaccines and Internet: characteristics of the vaccine safety net web sites and suggested improvements.
The Internet contains a large amount of useful information on many subjects, but also information of doubtful quality. To help identify Web sites on vaccine safety that fulfil good practice, the Global Advisory Committee on Vaccine Safety of the World Health Organization (WHO) has published criteria to which sites should adhere and a listing of Web sites that fulfil them. There are no studies describing the common attributes of these sites. To examine the attributes, design characteristics and resources of Web sites belonging to the Vaccine Safety Net (VSN) of the WHO. A cross-sectional, descriptive observational study using an evaluation questionnaire was carried out applied to the VSN web sites listed in March-April 2007. Twenty-six Web sites accredited by the VSN by April 2007 were analysed. With respect to design and quality, all sites contained information about the site manager. Postal and Email addresses were available for 84.6% of the sites. About privacy and personal data processing, 73.1% of sites specified the data protection procedure used and stated that data were not sold or passed third parties. The most-used language was English (76.9%). 96.3% of sites had links to other pro-vaccination sites and 19.2% provided the addresses of vaccination centres. 63.6% of webs were aimed at general public and health care workers but there was no clear separation of documents or different entry routes. With respect to information on vaccine safety, 84.6% of sites had information on adverse effects. In the general information section, 92.3% of sites had a new developments section. Some sites had multiple sources of financing and in 57% of sites, the financing was public. The most-important plus factors found were the transparency of financing, the lack of links to the pharmaceutical industry, the transparency of site management and responsibility and the proven scientific quality and constant updating of contents.


Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells.
Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene>4-chlorostyrene>4-fluorostyrene≈styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity.


Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK.
Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.


Propensity-score matched analysis comparing robot-assisted with laparoscopic partial nephrectomy.
To compare the peri-operative and early renal functional outcomes of robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) for kidney tumours. A total of 237 patients fulfilling the selection criteria were included, of whom 146 and 91 patients were treated with LPN and RAPN, respectively. To adjust for potential baseline confounders, propensity-score matching was performed. A favourable outcome was defined as a warm ischaemia time (WIT) of ≤20 min, negative surgical margins, no surgical conversion, no Clavien ≥3 complications and no postoperative chronic kidney disease (CKD) upstaging. Descriptive statistics and multivariable logistic regression analyses were performed before and after propensity-score matching. Within the propensity-score-matched cohort, the RAPN group was associated with significantly lower estimated blood loss (EBL; 156 vs 198 mL, mean difference [MD] = -42; P = 0.025), a shorter WIT (22.8 vs 31 min, MD = -8.2; P < 0.001) and a higher proportion of malignant lesions (88.4 vs 67.5%; odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.2-5.67; P = 0.023). With regard to early renal functional outcomes, the mean last estimated glomerular filtration rate was 95.8 and 89.4 mL/min per 1.73 m(2) (MD = 6.4; P = 0.01), with a mean ± sd percentage change of -4.8 ± 17.9 and -12.2 ± 16.6 (MD = 7.4; P = 0.018) in the RAPN and LPN groups, respectively. The intra-operative complication rate was significantly lower in the RAPN group (1.3 vs 11.7%; OR 0.1, 95% CI 0.01-0.81; P = 0.018). On multivariable analysis, surgical approach (RAPN vs LPN, OR 5.457, 95% CI 2.075-14.346; P = 0.001), Charlson Comorbidity Index (OR 0.223; 95% CI 0.062-0.811; P = 0.023), diameter-axial-polar score (OR 0.488, 95% CI 0.329-0.723; P < 0.001) and preoperative CKD stage (OR 3.189, 95% CI 1.204-8.446; P = 0.020) were found to be independent predictors of obtaining a favourable outcome. After adjusting for potential treatment selection biases, RAPN was found to be superior to LPN for peri-operative outcomes (EBL, WIT and intra-operative complications) and early renal functional preservation.


Moderate hypoxia modulates ABCG2 to promote the proliferation of mouse spermatogonial stem cells by maintaining mild ROS levels.
The aim of this study was to investigate the effects of different oxygen (O2) concentrations on the growth of mouse spermatogonial stem cells (SSCs) and the possible mechanisms of cell proliferation in vitro. The SSCs from testicular cells were cultured in various O2 concentrations (1%, 2.5%, 5%, and 20% O2) for 7 days. Colonies of SSCs were identified morphologically and by immunofluorescence. The number of mouse SSC colonies and the area covered by them were measured. Cell cycle progression of the SSCs was analyzed to identify the state of cell proliferation. The effects of O2 concentrations on the levels of intracellular reactive oxygen species (ROS) and expression of ATP binding cassette subfamily G member 2 (ABCG2) were also analyzed in the SSCs. Following culturing for 7 days, the SSCs were treated with Ko143 (a specific inhibitor of ABCG2) for 1 h, and the ROS level and expression of bcl-2, bax, and p53 were analyzed. The results showed that mouse SSCs formed compact colonies and had unclear borders in different O2 concentrations for 7 days, and there were no major morphologic differences between the O2 treatment groups. The expression of the SSC marker, GFR α1 was studied in each O2 treatment group. The number and area of SSC colonies, and the number of GFR α1 positive cells were the highest in the 2.5% O2 treatment group. Compared with other O2 concentrations, the number of cells in G0 cycle was significantly higher, while the level of intracellular ROS was lower at 1% O2. Moreover, the intracellular ROS levels gradually increased with increasing O2 concentration from 1% to 20%. The expression of ABCG2 in the SSCs cultured at 2.5% O2 was higher than in the other O2 groups. Inhibition of ABCG2 increased intracellular ROS generation, and the expression of the pro-apoptotic genes bax and p53, and decreased the expression of the anti-apoptotic gene bcl-2. In conclusion, moderate to low O2 tension increases ABCG2 expression to maintain mild ROS levels, triggers the expression of the anti-apoptotic genes, suppresses the proapoptotic gene pathway, and further promotes the proliferation of mouse SSCs in vitro.


Knockout of Matrix Metalloproteinase 2 Opposes Hypertension- and Diabetes-induced Nephropathy.
The progression of chronic kidney disease results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a broad-spectrum matrix metalloproteinase (MMP) inhibitor reduced renal injury in rat models of hypertension and diabetes. However, the isoforms and mechanisms involved are unclear. This study examined the role of MMP2 during the development of proteinuria and renal injury after induction of hypertension or diabetes in Dahl salt-sensitive (SS) and MMP2 knockout (KO) rats. Mean arterial pressure rose from 115 ± 2 to 145 ± 2 mm Hg and 116 ± 1 to 152 ± 3 mm Hg in MMP2 KO and SS rats fed a high-salt (8% NaCl) diet for 3 weeks. The degree of proteinuria, glomerular injury, renal fibrosis, and podocyte loss was lower in MMP2 KO rats than in SS rats. Blood glucose and HbA1c levels, and mean arterial pressure rose to the same extent in streptozotocin-treated SS and MMP2 KO rats. However, the degree of proteinuria, glomerulosclerosis, renal fibrosis, renal hypertrophy, glomerular permeability to albumin, and the renal expression of MMP2 and TGFβ1 were significantly reduced in MMP2 KO rats. Glomerular filtration rate fell by 33% after 12 weeks of diabetes in streptozotocin-treated SS rats compared with time-control rats, but glomerular filtration rate only fell by 12% in MMP2 KO rats. These results indicate that activation of MMP2 plays an essential role in the pathogenesis of hypertensive and diabetic nephropathy and suggests that an MMP2 inhibitor might slow the progression of chronic kidney disease.


Parathyroid Hormone Replacement Therapy in Hypoparathyroidism: A Meta-Analysis.
This study investigated the effect of human parathyroid hormone replacement therapy on specific disease-related outcomes in patients with hypoparathyroidism. Medline, Cochrane, EMBASE, and Google Scholar databases were searched until January 13, 2015 for randomized trials using the following search terms: hypoparathyroidism, parathyroid hormone/PTH, and hormone replacement therapy. Five randomized controlled trials (n=245) that investigated effect of either PTH (1-34) (3 trials) or PTH (1-84) (2 trials) on serum calcium, phosphate, 1, 25-dihydroxyvitamin D, 25-dihydroxyvitamin D levels, and urine level of calcium were included in the meta-analysis. Both PTH (1-34) and PTH (1-84) therapies were not associated with change in serum calcium level compared with calcitriol/placebo. The level of 24-h urine calcium excretion had a significant decrease in PTH (1-34)-treated group compared placebo/calcitriol (control) group (p≤0.012). PTH (1-34) did not change serum phosphate (p=0.053). PTH (1-84) did not change level of 24-h urine calcium excretion compared with control (p≥0.214) but it did decrease the levels of serum phosphorous (p=0.000). Both PTH-replacement therapies were not associated with change in serum 1,25-dihydroxyvitamin D level compared with control (p≥0.606), but were associated with a significant decrease in serum 25-dihydroxyvitamin D levels (p≤0.04). In conclusion, although the number of randomized trial is limited, our meta-analysis suggests that PTH (1-34) replacement therapy may maintain the serum calcium levels in the normal range by reducing the levels of urine calcium excretion, and both replacement therapies may maintain 1,25-dihydroxyvitamin D serum levels by reducing serum level of 25-dihydroxyvitamin D.


Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients.
The clinical findings and response to treatment of leptomeningeal metastases from solid tumors are analyzed in 90 patients treated at Memorial Sloan-Kettering Cancer Center during the period from January 1975 to February 1980. Patients included those who had either typical clinical findings of leptomeningeal tumor or conclusive laboratory evidence supporting the diagnosis. Carcinoma of the breast (46 patients), lung (23 patients) and melanoma (11 patients) were the common primary tumors. Symptoms of leptomeningeal metastasis occurred as the presenting sign in five patients and as late as ten years after the primary tumor was diagnosed in four other patients. Most patients had active systemic disease outside the nervous system. Signs and symptoms could be classified as involving either the brain, cranial nerves, or spinal nerves. Most patients had either symptoms or signs in more than one area at the time the diagnosis was established. The initial spinal fluid examination was abnormal in all but three patients, but only 49 had cytologic evidence of leptomeningeal metastases. Repeated spinal fluid assay yielded a positive cytology in 82 patients. Measurement of biochemical markers, including beta-glucuronidase, carcinoembryonic antigen and lactic dehydrogenase, assisted in the diagnosis. Approximately half of the patients treated by intraventricular methotrexate experienced improvement or stabilization of neurological symptoms for more than a month; median survival was 5.8 months after diagnosis, with a range of 1--29 months. In 18 patients disease was limited to the nervous system, and median survival was eight months, with four patients surviving one year and two patients for two years. Side effects of therapy were, for the most part, minor. We conclude that vigorous treatment of leptomeningeal metastases with intrathecal chemotherapeutic agents improves symptomatology in some patients, and at times prolongs survival.


Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study.
The antidepressant activity of citalopram (R,S-CIT) is mainly due to its (S)-enantiomer (S-CIT). P-glycoprotein (P-gp), encoded by the ABCB1 gene, is a membrane transport protein which regulates the efflux of many drugs. Polymorphisms in the ABCB1 gene may have an impact on the expression and function of P-gp, thereby influencing the response to treatment with antidepressants, which are substrates of this protein. The influence of ABCB1 polymorphism on the disposition of R,S-CIT in plasma and cerebrospinal fluid (CSF) was examined under steady-state conditions in 15 patients with major depression treated with 40 mg/d R,S-CIT for 4 weeks. In contrast to the ABCB1 C3435T polymorphism, only the ABCB1 G2677T polymorphism significantly influences R,S-CIT plasma and CSF concentrations (46+/-11 ng/ml versus 69+/-20 ng/ml for TT versus GT/GG in plasma, p=0.027; 24+/-5 ng/ml versus 32+/-9 ng/ml for TT versus GT/GG in CSF, p=0.05). On the other hand, no significant influence of G2677T polymorphism was found on the plasma and CSF (S)/(R) ratio, suggesting a lack of stereoselectivity in the activity of this transporter. The 2677 GG/GT genotype was associated with a better treatment response (p=0.001) compared with 2677TT genotype. Furthermore, higher R,S-CIT plasma and CSF concentrations were observed in treatment responders. This study is the first to demonstrate that a P-gp polymorphism significantly influences plasma and CSF concentrations of R,S-CIT in depressive patients, therefore possibly influencing the activity of this antidepressant. These findings should be replicated in future studies with larger groups of patients. Because of the small number of subjects in the present study, future studies with larger groups of patients, also with different ethnicities.


The Diagnostic Utility of Volatile Organic Compounds in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.
Volatile organic compounds (VOCs) show promise as potential biomarkers of for ulcerative colitis and Crohn's disease, two chronic idiopathic gastrointestinal disorders with diagnostic and management challenges. Non-invasive biomarkers aid early diagnosis and management. In this study we review studies of diagnostic accuracy of VOCs in inflammatory bowel disease. A systematic search was carried out on the Pubmed and Scopus databases; with sixteen studies reviewed and meta-analysis carried out on ten. Meta analysis of 696 IBD cases against 605 controls revealed a pooled sensitivity and specificity of 87% (95% CI, 0.79 - 0.92) and 83% (95% CI, 0.73 - 0.90) respectively. AUC was 0.92. VOCs perform very well as non-invasive biomarkers of IBD; with much scope for future improvement and research.


Opportunities and challenges in developing Alzheimer disease therapeutics.
Alzheimer disease (AD) is a chronic, progressive disorder with an average disease progression of 7-10 years. However, the histopathological hallmark lesions of this disease, the extracellular Aβ plaques and the intraneuronal neurofibrillary tangles, start as early as childhood in the affected individuals. AD is multifactorial and probably involves many different etiopathogenic mechanisms. Thus, while AD offers a wide window of opportunity that practically includes the whole life span of the affected individuals, and numerous therapeutic targets, the multifactorial nature of this disease also makes the selection of the therapeutic targets an immensely challenging task. In addition to β-amyloidosis and neurofibrillary degeneration, the AD brain also is compromised in its ability to regenerate by enhancing neurogenesis and neuronal plasticity. An increasing number of preclinical studies in transgenic mouse models of AD show that enhancement of neurogenesis and neuronal plasticity can reverse cognitive impairment. Development of both drugs that can inhibit neurodegeneration and drugs that can increase the regenerative capacity of the brain by enhancing neurogenesis and neuronal plasticity are required to control AD.


The Scottish first episode schizophrenia study. VII. Two-year follow-up. Scottish Schizophrenia Research Group.
Of 49 schizophrenic patients followed up 2 years after their first admission to hospital, 37% were well, 47% had been readmitted to hospital at some time over the 2 years, and 38% showed schizophrenic symptoms at follow-up. A poor outcome at 2 years was associated with male sex, poor outcome after the first 5 weeks of the first admission, negative schizophrenic symptoms on first admission, and a diagnosis of definite or probable schizophrenia using the Feighner criteria. Only 23% were in employment. A small double-blind discontinuation study of maintenance antipsychotic medication during the second year found more relapses in those switched to placebo medication. Repeat psychometric assessment at 2 years confirmed modest improvements found at 12 months; that is, there was no evidence of intellectual decline. Relatives showed no more psychosocial distress than that found in a normal community sample; what distress there was correlated with patients' schizophrenic symptoms.


Physical violence against women: evaluation of women assaulted by spouses.
To investigate the characteristic of physical violence against women sent to the Forensic Medicine Council for the forensic reports with a history of being assaulted by their spouses. One hundred and thirty five women attending judicial institutions from August 1st 2000 to January 31st 2001 were interviewed. The demographic characteristics of assaulted women and their spouses, time of violence, beginning and continuation of violence after marriage, frequency of violence, women's judgment of the reason for being assaulted, violence against children by the husbands, history of violence in the husbands' family, the husbands' manner at home, women' attitudes against violence, existence and type of physical trauma and injury severity according to Turkish Penalty Law were evaluated. The data were analyzed using chi(2) test and percent ratios. The majority of both women and their husbands had been born in rural areas (73.3% and 71.1%, respectively). Approximately three quarters of the men and women had secondary school or lower education levels (80.7% and 81.5%, respectively). Most women (63.7%) and 17.8% of men were unemployed. For the most part, women were assaulted between 18.01 and 06.00 h (73.3%). Nearly 80% of husbands had at least one 'bad' habit such as alcohol intake and gambling. 60.7% of the assaulted women did not react to their spouses' violence. The most frequently encountered result of violence was soft tissue lesions (91.9%). After being assaulted nearly all of the women (91.9%) were provided with forensic reports advising of between 1 and 7 days of inability to follow ordinary pursuits. Women from all socioeconomic-cultural levels reported a history of partner violence. Routine screening with structured questions during visits to doctors is necessary in order to identify assaulted women so as to prevent potential violence and to interrupt existing violence.


A New Modeling Method to Characterize the Stance Control Function of Prosthetic Knee Joints.
Biomechanical models can inform design and optimization of prosthetic devices by connecting empirically derived biomechanical data to device design parameters. A new method is presented to characterize the function of prosthetic stance control under mobility conditions associated with activities of daily living. The method is based on a model of the gait modes corresponding to finite stance control states. Empirical data from amputee and simulated gait were acquired using a custom-built wearable instrument and input into the model. The modeling approach was shown to be robust, responsive, and capable of accurate characterization of controller function under diverse locomotor and prosthetic setup conditions. Future work is focused on the development of a fully self-contained wearable system, to facilitate collection of large datasets across a variety of user demographics, controller designs, and activities of daily living. The method offers predictive capability, which can assist in the virtual testing of new designs or modifications.


The spectrum of primary blastomycotic meningitis: a review of central nervous system blastomycosis.
Three cases of meningitis with initial and exclusive neurological involvement prompted a review of the clinical, cerebrospinal fluid, and pathological findings in an additional 78 patients with central nervous system blastomycosis. The first patient of the 3 had progressive cerebellar dysfunction as the result of chronic basilar meningitis. The second had a C8-T1 radiculopathy without other evidence of superior sulcus syndrome, and subsequent acute fatal meningitis. The third had aseptic, benign, self-limited meningitis followed by clinically obvious systemic blastomycosis. Diagnosis is difficult, and it is likely that other cases have been presumptively treated for tuberculous meningitis. A more aggressive approach to diagnosis is proposed that takes into account the condition of the patient, the likelihood of dissemination at necropsy, and the frequent meningeal infections that are negative on culture of lumbar CSF.


Prediction of 5-fluorouracil and cisplatin synergism for advanced gastrointestinal cancers using a collagen gel droplet embedded culture.
The combination effects of 5-fluorouracil (5-FU) and cisplatin (CDDP) are herein reported using a drug sensitivity assay, with a special focus on the induction of apoptosis. The combination effects of 5-FU and CDDP were examined using in vitro chemosensitivity testing by means of the collagen gel droplet embedded culture drug sensitivity test (CD-DST) in MKN45 and GSS cell lines, and primary gastrointestinal cancer cells ob-tained from 40 patients. Apoptosis was assayed using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin neck end labeling (TUNEL) method. The combination of 5-FU with CDDP increased the efficacy of 5-FU 1.16-1.35-fold with the GSS cell line and 1.10-2.01-fold with primary gastric and colorectal cancers when the exposure time was 7 days. In primary tumor cells a synergistic action was noted in 15 of 40 (38%) gastric and colorectal cancers. Both 5-FU and CDDP were found to induce apoptosis in GSS and MKN45 cells, and the number of apoptotic cells increased synergistically after the combined treatment in the GSS cases and showed a correlation with the results of CD-DST. Our findings suggested that the efficacy of the combined treatment with 5-FU and CDDP can be predicted by the in vitro chemosensitivity test and that a synergistic effect might be associated with the induction of apoptosis.


Fucus vesiculosus polysaccharide alleviates type 2 diabetes in rats via remodeling gut microbiota and regulating glycolipid metabolism-related gene expression.
The antidiabetic activity and underlying mechanisms of Fucus vesiculosus polysaccharide (FVP) were studied in type 2 diabetic rats. Our results exhibited that FVP intervention reversed body weight loss, alleviated hyperglycemia and insulin resistance in diabetic rats. FVP also had the potential to ameliorate dyslipidemia, liver and kidney dysfunction, decrease oxidative stress, promote glycogen synthesis, and boost short-chain fatty acid production and total bile acid excretion. 16S rRNA gene sequencing analysis suggested that FVP interfered with the gut microbiota in a beneficial manner. Moreover, RT-qPCR results demonstrated that the antidiabetic activity of FVP in connection with the acceleration of blood glucose absorption and glycogen synthesis, the inhibition of gluconeogenesis, and the regulation of lipid metabolism in the liver. These findings suggested that FVP had antidiabetic effects on high-fat diet and STZ-induced diabetic rats and could be a potential resource for treating type 2 diabetes mellitus.


The effect of growth retardation and of osteomalacia on the uptake of albumin by bone.
125I-labeled rat albumin injected intravenously into rats was taken up by growing bone. Some of this radioactive albumin could be removed from bone by washing with saline, the proportion so removed decreasing from 82.5% at 1 day to 7.4% at 8 days. Both the total radioactivity, and that remaining in bone after saline wash, were reduced when growth was slowed by alteration or restriction of the diet. Although the amount of 125I albumin in rachitic bone was reduced, autoradiography showed that radioactivity was present in rachitic osteoid. Immunoprecipitation using anti-rat-albumin serum showed that about half of the radioactivity released from normal bone by EDTA was still attached to albumin. These results suggest that albumin plays some part in the growth of bone.


Nurse managers' views regarding patients' long waiting time at community health centers in Gauteng Province, South Africa.
Patients' long waiting time still exceeds the set target of 120 minutes. As a result, the volume of complaints remains a concern that points to systems inefficiencies. Minimal attention has been given to the experiences of nurse managers regarding patients' long waiting time. To explore and describe the experiences of nurse managers regarding patients' long waiting time at Community Health Centers (CHCs) in Gauteng Province, South Africa. The research applied qualitative exploratory descriptive and contextual design. Non-probability purposive sampling techniques were used to select eight nurse managers. Individual semi-structured interviews were conducted and captured with an audio tape. Tesch's 8-steps of data analysis were followed to analyze the data. Three themes and seven categories emerged from the study: (1) The adverse effects of patients' long waiting time (early birds to evade long queues, increased patients' complaints and compromised quality care), (2) Factors that contribute to patients' long waiting time (records and patient administration system deficiencies, poor time management, patients' lack of adherence to booking system), (3) Measures to mitigate patients' long waiting time (embracing decongestion systems to mitigate patients' overflow at CHC). The study recommends the optimal implementation of an appointment system to avert long waiting times. Collaboration between CHCs' management and clinic committees is encouraged to provide the best solutions to the reduction of patients' long waiting times. In addition, time management is one area that needs to be improved. A digital record management system can assist in better-sought problems related to filling. Studies are encouraged on a model to enhance collaboration in reduction of patients' long waiting time.


Rural and Indigenous Vulnerable Populations: A Case Study.
This is an actual case study of a young Native American man. The names have changed but the challenges remain the same. The intersectionality between the Native population, a rural community, and poverty intersects to create a compelling look at the challenges people face in these communities. Implications for Nursing in relation to practice, education, and policy are addressed.


Increased NDRG1 expression is associated with advanced T stages and poor vascularization in non-small cell lung cancer.
N-myc downstream regulated gene 1 (NDRG1) is a member of the N-myc downstream regulated gene family which belongs to the alpha/beta hydrolase superfamily. Earlier studies have shown its association with inhibition of tumor metastasis. However, its function in malignant tumors is not fully enunciated. Recently there was increasing evidence that NDRG1 is involved in stress responses. In the current study, we examined the expression of NDRG1 and its correlation with clinicopathological factors and microvessel density (MVD) in non-small cell lung cancer (NSCLC) using immunohistochemistry (IHC). NDRG1 expression in NSCLC (71/115, 61.7%) was higher than that in normal lung tissues (32/115, 27.8%) (p < 0.05). NDRG1 expression in NSCLC cells was found in cytoplasm (63/115, 54.8%), nuclear (24/115, 20.9%) and cell membrane (13/115, 11.3%). NDRG1 expression in NSCLC with advanced T stages (T2-4) (63/84, 75.0%) was significantly higher than that with T1 stage (8/31, 25.8%) (P < 0.05). No other clinicopathological factors including lymph node metastasis were found to be associated with NDRG1 expression (p > 0.05). Moreover increased NDRG1 expression was associated with lower MVD in NSCLC (P < 0.05). MVD in adenocarcinoma (33.4 ± 8.4/HP) was significantly higher than that in squamous cell carcinoma (SCC) (19.3 ± 8.1/HP) (P < 0.05). No other clinicopathological factors were associated with MVD in NSCLC (p > 0.05). The present findings indicate an increase of NDRG1 expression with the progress of tumour extent which may be due to unbalanced tumor oxygenation on account of poor vascularization in NSCLC.


Effects of UV radiation on motility, photo-orientation and pigmentation in a freshwater Cryptomonas.
The effects of UV radiation on photo-orientation, motility and pigmentation have been studied in a freshwater Cryptomonas species. The cells show a pronounced diaphototactic orientation which is affected by UV radiation at 50 mW m-2 within about 90 min. Both the average velocity of the swimming cells and the percentage of motile cells within the population decrease within about the same exposure time. UV radiation also bleaches the cellular pigments.


FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread.
Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. In 20/30 patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.


Ultrastructural study of satellite lymph nodes in syphilitic rabbits.
In an electron microscopy study of lymph nodes from syphilitic rabbits plasmablasts and plasma cells were unequivocally identified in germinal centres. Up to 20% of the plasma cells possessed unusual cytological features. Paracortical hypoplasia was shown to be associated with actively phagocytic histiocytes. These findings may reflect morphological correlates of the aberrant immune regulation which has been observed in infection with Treponema pallidum.


Direct growth of novel alloyed PtAu nanodendrites.
A novel nanostructure of a PtAu catalyst, alloyed PtAu nanodendrites, has been synthesized via a reproducible single-step hydrothermal co-reduction of Pt and Au inorganic precursors and shows exceptionally high catalytic activity towards the electrooxidation of formic acid.


Characterization of the glycoprotein D gene products of equine herpesvirus 1 using a prokaryotic cell expression vector.
The gene encoding equine herpesvirus 1 (equine abortion virus; EHV-1) glycoprotein D was engineered into the prokaryotic vector pEX, and expressed as a beta-galactosidase fusion product, which was recognized by pooled equine sera and anti-EHV-1 rabbit sera. Antibodies raised against the EHV-1 gD fusion product identified strong bands in infected cells at 66 and 68 K and at 138 K in purified virus, thus characterizing the several forms of this major envelope glycoprotein which is an important candidate for inclusion in subunit vaccines.


Virtually the same? Examining the impact of the COVID-19 related shift to virtual lung cancer multidisciplinary team meetings in the UK National Health Service: a mixed methods study.
To evaluate the impact of the shift to virtual lung cancer multidisciplinary team meetings (MDTMs) in response to the COVID-19 pandemic, specifically in relation to the magnitude of information technology (IT) issues and distractions and MDT members'/managers' perceptions and experiences of this shift. A mixed methods study comprising real-time observations of IT issues/distractions within virtual MDTM case discussions held between April and July 2021 and qualitative data from interviews/surveys. Eight hospital organisations in Southern England. Team members (respiratory physicians, surgeons, oncologists, radiologists, pathologists, palliative care professionals, nurses and MDT coordinators) and managers (n=190) across 8 local MDTs. MDTM observations (n=1664) highlighted significant variation between teams regarding IT functionality. IT issues and other distractions relating to the virtual MDTM format were observed 465 times affecting 20.6% of case discussions, most of which were audio issues (18.1%). Case discussions that had audio issues were, on average, 26 s longer (t(1652)=-2.77, p<0.01). A total of 73 MDT members and managers participated in the survey and 41 participated in interviews, with all 8 teams being represented. Increased flexibility, reduced travel time and easier real-time access to patient information were seen as the main advantages of virtual MDTMs. Views regarding the impact on relational aspects and communication differed. In line with observational findings, concerns were raised in relation to IT, including having inappropriate equipment, insufficient bandwidth (impairing image sharing and video communication) and an overarching theme that virtual meeting platforms provided were not fit for purpose. Despite the potential benefits of virtual MDTMs, IT issues can waste valuable MDTM time. If hospital organisations plan to continue virtual MDTMs, a functioning infrastructure is required, necessitating appropriate resource and investment.


Synthetic and endogenous testosterone conjugates: acid hydrolysis studied by radioimmunoassay.
The acid hydrolysis of synthetic testosterone sulphate and glucuronide by sulphuric acid has been studied by measuring the release of uncojugated testosterone by radioimmunoassay. The sulphate was hydrolyzed at lower concentration of acid but no conditions were found where only the sulphate was completely hydrolyzed without any hydrolysis of the glucuronide. Results of similar studies on human urine, however, suggested that human urine contains three conjugates of testosterone and 5 alpha-dihydrotestosterone: the sulphate and glucuronide and also a very acid labile conjugate hitherto unknown. Hydrochloric acid has stronger hydrolyzing effect at the same normality and released more unconjugated testosterone in urine at the same pH than did sulphuric acid. A complete hydrolysis of urinary conjugates in 3 molar sulphuric acid was accomplished without destruction of immunoassayable testosterone and constitutes a suitable method for the determination of the total testosterone content in urine. The method was compared with other hydrolyzing methods by measuring the testosterone release from urinary conjugates after their extraction and separation by by thin-layer chromatography.


Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle.
Cancer and proliferating cells exhibit an increased demand for glutamine-derived carbons to support anabolic processes. In addition, reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) was recently shown to be a major source of citrate synthesis from glutamine. The role of NAD(P)H/NAD(P)(+) cofactors in coordinating glucose and glutamine utilization in the tricarboxylic acid (TCA) cycle is not well understood, with the source(s) of NADPH for the reductive carboxylation reaction remaining unexplored. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial enzyme that transfers reducing equivalents from NADH to NADPH. Here, we show that knockdown of NNT inhibits the contribution of glutamine to the TCA cycle and activates glucose catabolism in SkMel5 melanoma cells. The increase in glucose oxidation partially occurred through pyruvate carboxylase and rendered NNT knockdown cells more sensitive to glucose deprivation. Importantly, knocking down NNT inhibits reductive carboxylation in SkMel5 and 786-O renal carcinoma cells. Overexpression of NNT is sufficient to stimulate glutamine oxidation and reductive carboxylation, whereas it inhibits glucose catabolism in the TCA cycle. These observations are supported by an impairment of the NAD(P)H/NAD(P)(+) ratios. Our findings underscore the role of NNT in regulating central carbon metabolism via redox balance, calling for other mechanisms that coordinate substrate preference to maintain a functional TCA cycle.


Sixth Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: The Society Of Thoracic Surgeons Pedimacs Annual Report.
The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by The Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ventricular assist devices (VADs). From September 19, 2012, to December 31, 2021, there were 1355 devices in 1109 patients (<19 years) from 42 North American Hospitals. Cardiomyopathy was the most common underlying cause (59%), followed by congenital heart disease (25%) and myocarditis (9%). Regarding device type, implantable continuous (IC) VADs were most common at 40%, followed by paracorporeal pulsatile (PP; 28%) and paracorporeal continuous (PC; 26%). Baseline demographics differed, with the PC cohort being younger, smaller, more complex (ie, congenital heart disease), and sicker at implantation (P < .0001). At 6 months after VAD implantation, a favorable outcome (transplantation, recovery, or alive on device) was achieved in 84% of patients, which was greatest among those on IC VADs (92%) and least for PC VADs (69%). Adverse events were not uncommon, with nongastrointestinal bleeding (incidence of 14%) and neurologic dysfunction (11% [stroke, 4%]), within 2 weeks after implantation being the most prevalent. Stroke and bleeding had negative impacts on overall survival (P = .002 and P < .001, respectively). This Sixth Pedimacs Report demonstrates the continued evolution of the pediatric field. The complexity of cardiac physiologies and anatomic constraint mandates the need for multiple types of devices used (PC, PP, IC). Detailed analyses of each device type in this report provide valuable information to further advance the care of this challenging and vulnerable population.


Continuous central venous saturation monitoring in pediatrics: a case report.
To report the use of a new pediatric central venous catheter that offers continuous central venous saturation (ScVO2) monitoring in the critically ill child. Case report. Pediatric intensive care unit in a tertiary care children's hospital. A 3-month-old child, following cardiac surgery, with an isolated decrease in central venous saturations. Diagnosis of pericardial effusion by echocardiography followed by surgical drainage. ScVO2 readings quickly returned to normal, and the remaining patient course was uneventful. We report the first case of a newly modified central venous catheter (PediaSat Oximetry Catheter, Edwards Lifesciences LLC, Irvine, CA) for children and demonstrate its utility in a patient with impaired oxygen delivery when traditional markers remain stable. This catheter enabled the rapid diagnosis of cardiac compromise due to pericardial effusion, leading to early treatment. Traditional central catheter functions and insertion technique are maintained, making the catheter potentially useful in any critically ill child.


Prospective randomized comparison of left atrial and biatrial radiofrequency ablation in the treatment of atrial fibrillation.
The aim of this study was to compare, in patients with permanent atrial fibrillation (AF), the efficacy and safety of left atrial ablation with that of a biatrial procedure and to assess the risk factors for late failure of sinus rhythm restoration. Between January 2004 and January 2007, 299 consecutive patients underwent the radiofrequency ablation procedure for AF associated with concomitant cardiac surgery. According to a prospective, open, and randomized trial, 149 patients underwent left atrial plus cavotricuspid isthmus ablation (left atrial group), while 150 patients underwent biatrial ablation (biatrial group). The postoperative and mid-term follow-up results were compared between the two groups. Both univariate and multivariate analyses were used to assess the risk factors for late recurrence of AF. There were seven in-hospital deaths (2.3%), including two in the left atrial group (1.3%) and five in the biatrial group (3.3%), and there were no differences in the incidence of the mortality and complications during the postoperative and follow-up periods between the groups. At discharge, sinus rhythm was maintained in 77.1% of the patients, including 78.2% of those in the left atrial group and 75.9% in the biatrial group (p=0.68). Follow-up was completed in 97% of the patients, with a mean time of 28+/-5 months. At the latest follow-up, two deaths occurred in the biatrial group. Sinus rhythm was documented in 237 (85.0%) out of all the patients, including 85.2% (121/142) in the left atrial group and 84.1% (116/138) in the biatrial group patients (p=0.87). Using a multivariate analysis, a left atrial diameter of >/=80 mm (p=0.02) was an independent predictor for a late recurrence of AF. Both the left atrial combined with cavotricuspid isthmus ablation and biatrial maze procedure is safe and effective in treating patients with AF, with an acceptable sinus conversion rate, mortality and morbidity. A left atrial dimension of >/=80 mm was a significant predictor for a late recurrence of AF.


Effects of fenofibrate treatment on fatty acid oxidation in liver mitochondria of obese Zucker rats.
Obese Zucker rats were dosed orally for one week with fenofibrate (100 mg/kg). Liver weights of treated rats as expressed as percent of body weight were slightly increased, while protein, DNA and lipid contents were unaffected per g of liver or increased when expressed in whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly increased by fenofibrate both per g of liver and per total liver, while urate oxidase activity was unchanged when expressed per g of liver. The activity of monoamine oxidase and that of cytochrome c oxidase used as marker enzymes for mitochondria were increased only when expressed per total liver. However, fenofibrate treatment induced a pronounced increase in the activities of mitochondrial palmitoyl-CoA dehydrogenase and carnitine acyltransferases, particularly carnitine acetyltransferase. Fenofibrate also caused a significant increase of carnitine content in liver and hepatic mitochondria. The greatest observed increases were in free carnitine and in the rate of carnitine-dependent oleate oxidation, which might be favoured in vivo by a lesser sensitivity of CPT-I to a malonyl-CoA inhibitory effect. The present results suggest that fenofibrate treatment induces increased hepatic mitochondrial beta-oxidation in obese Zucker rats.


Comparison of the incidence of pathogenic and antibiotic-resistant Escherichia coli strains in adult cattle and veal calf slaughterhouse effluents highlighted different risks for public health.
The goal of this study was to investigate the involvement of bovine slaughterhouse effluents and biosolids in the risk of environmental dissemination of pathogenic and antibiotic-resistant Escherichia coli. Several samples were collected from one adult cattle and one veal calf slaughterhouse wastewater treatment plant (WWTP). The treatment process had no impact on the percentage of Shiga toxin-producing E. coli (STEC) and on the percentage of atypical enteropathogenic E. coli (aEPEC). A STEC O157:H7 was isolated from the thickened sludge of the adult cattle slaughterhouse. As thickened sludge is intended to be spread on agricultural lands, the detection of this pathogenic strain is a public health issue. The percentage of antibiotic-resistant E. coli was 5.0% and 87.5% in wastewater from the adult cattle and the veal calf slaughterhouse, respectively. These percentages were not significantly different after treatment. Integron-bearing E. coli isolates were only detected in the veal calf slaughterhouse WWTP with percentages above 50.0% for all sampling points whatever the step of the treatment process. Taken together, these findings highlighted the fact that different public health risks might be associated with adult cattle or veal calf slaughterhouses regarding the dissemination of pathogenic and antibiotic-resistant E. coli isolates into the environment.


Developing functionalized dendrimer-like silica nanoparticles with hierarchical pores as advanced delivery nanocarriers.
Functionalized dendrimer-like hybrid silica nanoparticles with hierarchical pores are designed and synthesized. The unique structure, large surface area, and excellent biocompability render such materials attractive nanocarriers for the advanced delivery of various sized drugs and genes simultaneously.


A combined measurement of metal bioaccumulation and condition indices in juvenile European flounder, Platichthys flesus, from European estuaries.
Condition indices and metal bioaccumulation of early life stages of juvenile flounder (5-10 cm) were determined in three anthropogenic estuaries (the Scheldt, Seine and Loire) and compared to a reference site (the Canche). Significant correlations were found between metal concentrations in sediment and (i) fish liver for Cd, Cu, Ni, Pb, V and Zn and (ii) fish gills for Cd and Mn. Metal accumulation in juvenile flounder from the three anthropogenic estuaries coincided with significantly lower Fulton's K indices (from 0.99 ± 0.03 to 1.06 ± 0.01 mg mm(-3)) compared to those from the Canche estuary (from 1.02 ± 0.01 to 1.13 ± 0.01 mg mm(-3)). This discrepancy in fish condition index increased with fish size and therefore, strongly depends on the time juvenile spend in estuary. Muscle lipid contents and Triacylglycerol to Sterol ratios were significantly lower in fish collected in the Scheldt (lipid content: 21.3 ± 3.6%), Seine (17.9 ± 19.8%) and Loire (19.5 ± 2.4%) estuaries compared to those originating from the Canche (38.3 ± 4.6%). This study highlights that combined measures of both fish metal contents and condition indices gives a relevant assessment of juvenile fish health growing in anthropogenic estuaries.


Development and internal validation of a multivariable risk prediction model for severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block.
Rebound pain occurs after up to 50% of ambulatory surgeries involving regional anaesthesia. To assist with risk stratification, we developed a model to predict severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block. After ethics approval, we performed a single-centre retrospective cohort study. Patients undergoing lower limb surgery with popliteal sciatic nerve block from January 2016 to November 2019 were included. Exclusion criteria were uncontrolled pain in the PACU, use of a perineural catheter, or loss to follow-up. We developed and internally validated a multivariable logistic regression model for severe rebound pain, defined as transition from well-controlled pain in the PACU (numerical rating scale [NRS] 3 or less) to severe pain (NRS ≥7) within 48 h. A priori predictors were age, sex, surgery type, planned admission, local anaesthetic type, dexamethasone use, and intraoperative anaesthesia type. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), Nagelkerke's R2, scaled Brier score, and calibration slope. The cohort included 1365 patients (mean [standard deviation] age: 50 [16] yr). The primary outcome was abstracted in 1311 (96%) patients, with severe rebound pain in 652 (50%). Internal validation revealed poor model performance, with AUROC 0.632 (95% confidence interval [CI]: 0.602-0.661; bootstrap optimisation 0.021), Nagelkerke's R2 0.063, and scaled Brier score 0.047. Calibration slope was 0.832 (95% CI: 0.623-1.041). We show that a multivariable risk prediction model developed using routinely collected clinical data had poor predictive performance for severe rebound pain after foot and ankle surgery. Prospective studies involving other patient-related predictors are needed. NCT05018104.


Discriminating smooth from grooved surfaces: effects of random variations in skin penetration.
The ability to discriminate a smooth surface from a grooved one depends on several variables, including the width of the grooves and the force with which the skin is contacted. It has been hypothesized that this smooth-grooved discrimination with statically presented stimuli is based on intensity cues, namely, the overall difference in perceived intensity between the smooth and grooved surfaces. To test this hypothesis, the perceived intensities of test stimuli were varied on a trial-by-trial basis by varying the depth of penetration the contactor was allowed to travel into the skin. As compared to a control condition in which stimuli were presented with the same average penetration and contrary to the hypothesis, random variations in penetration produced no decline in smooth-grooved performance. The total amount of conformance was an accurate predictor of sensitivity across various penetrations and across two test sites (distal finger pad and finger base). It appears that subjects are making absolute rather than comparative judgments in the smooth-grooved task. A recently developed continuum mechanical model of the responses of first-order mechanoreceptive afferents to static stimuli provided both a good fit to the data and indicated what aspect of the peripheral neural image was relevant for discriminating smooth surfaces from grooved surfaces.


Studies toward welwitindolinones: formal syntheses of N-methylwelwitindolinone C isothiocyanate and related natural products.
The formal syntheses of N-methylwelwitindolinone C isothiocyanate (4) and several other welwitindolinones 5-8 were achieved by the independent synthesis of 79. The synthesis featured a Lewis acid-mediated coupling between a heteroaryl carbinol and bis-TMS enol ether, an intramolecular enolate arylation, and an unprecedented intramolecular allylic alkylation of a γ-acyloxyenone.


Heightened psychobiological reactivity to laboratory stressors in healthy women at familial risk for breast cancer.
This study examined the possibility that reactivity to acute stressors may be altered among women facing the chronic stress of being at familial risk for breast cancer. Sixteen healthy women with histories of breast cancer in their families (Risk Group) and 32 women at normal risk (Comparison Group) were exposed to 15 min of classic laboratory stressors. Seventeen women at normal risk were randomly assigned to nonstressful tasks (manipulation check). Self-reported distress, natural killer cell activity (NKCA), and NK cell numbers (percentage of CD3-CD16/56+ lymphocytes) were assessed before and after the tasks. Cardiovascular activity was assessed throughout the session. The tasks elicited increases in distress, heart rate, NKCA, and NK cells numbers in both experimental groups. Supporting study hypotheses, the Risk Group had larger increases in distress, heart rate, NKCA, and NK cell numbers. These findings raise the possibility that the chronic stress associated with familial cancer risk may have negative health consequences through changes in psychobiological reactivity.


A dual pathway for the transmission of spongiform encephalopathy disease.
The nature of the infective process in the transmissible spongiform encephalopathy (SE) diseases has been a longstanding problem--in particular, whether the causative agents are (unusual) nucleic-acid-mediated viruses, or replicating non-nucleic acid molecules such as protein. Although there is much (conflicting) evidence supporting both views, it does not seem to have been considered that many of the outstanding problems could be resolved if both mechanisms are operating--either separately or together--i.e. that there is a dual, but interconnected, pathway leading to disease development. It is suggested that this is in fact the case, and the implications are discussed.


Pituitary apoplexy in the setting of coronary angiography.
Pituitary apoplexy (PA) is a rare but potentially life-threatening event. Typically, it results from hemorrhage into a pituitary adenoma, although cases affecting the intact gland have been reported. PA may occur spontaneously or in a setting of certain diagnostic and therapeutic procedures. The association of PA and contrast administration in the setting of neuroimaging have been postulated. The authors report a case of PA following coronary angiography. To the best of the authors' knowledge, this scenario has not been previously reported. A 66-year-old woman with a congenital septal defect underwent coronary angiography that was technically uncomplicated. After the procedure, the patient experienced retro-orbital pain and developed ophthalmoplegia. Magnetic resonance imaging (MRI) showed a hemorrhagic sellar mass extending into the cavernous sinus. A 3-month follow-up MRI revealed cystic changes. The patient expired 4 months later because of cardiorespiratory failure. PA in the absence of adenoma was confirmed on autopsy. The authors hypothesize that apoplexy here was related to the administration of Omnipaque in combination with the anticoagulation effect of heparin.


The effect of clonidine on centrally and peripherally evoked submaxillary salivation.
In anaesthetised cats, clonidine (10 microgram/kg, i.v.) produced a 60% reduction in submaxillary salivation induced by brain stem stimulation at 10 and 15 Hz and reductions of 35 and 15% in salivation evoked by chorda tympani nerve stimulation at 5 and 15 Hz respectively. Pretreatment with clonidine (20 microgram/kg/day, orally) for 28 days reduced peripherally evoked salivation by 45%. These results suggest that both central and peripheral mechanisms are involved in the diminished salivation produced by clonidine, and the reduction on peripheral stimulation may reflect the presence of presynaptic alpha-adrenoceptors inhibiting cholinergic transmission.


The use of pyloric exclusion in the management of severe duodenal injuries.
Repair of severe duodenal injuries often constitutes a technical challenge, and a variety of special technics have been described. For the past seven years we have utilized temporary pyloric exclusion and gastrojejunostomy to produce "diverticulization" of the duodenum. This procedure was utilized in seventy-five patients selected from 175 consecutive patients presenting with duodenal trauma. The mortality was 19 per cent and the rate of fistula formation was 5 per cent in this series and 14 per cent and 2 per cent, respectively, in the overall series. Follow-up studies of gastric physiology and functional anatomy show no evidence of alteration of these parameters. We thus believe that patients presenting with severe duodenal trauma and often multiple devastating associated organ injuries can be adequately treated with this procedure with a significant decrease in mortality and with marked improvement of postoperative morbidity.


Mortality outcomes and 30-day readmissions associated with coronary artery aneurysms; a National Database Study.
The literature on prevalence and outcomes of coronary artery aneurysm (CAA) in the United States (US) is limited. To study the prevalence, outcomes, and trends of CAA. Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the US were analyzed for CAA among coronary angiography (CA) related hospitalizations for the years 2012-2018. A total of 6,843,910 index CA related hospitalizations were recorded for the years 2012-2018 in the NRD (Mean age 64.37 ± 13.30 years' 38.6% females). Of these 9671 (0.141%) were CAA, 5092 (52.7%) without-ACS and 4579 (47.3%) with ACS [NSTEMI occurred in 2907(63.5%) and STEMI in 1672(36.5%)]. In-hospital mortality among CAA was comparable to those without-CAA on angiography (n-209,2.17% vs n = 175,120,2.56%;p = 0.08). CAA patients who presented with ACS vs those without ACS had higher mortality (n = 150,3.28%vsn = 60,1.16%;p < 0.001) cardiogenic shock 6.9%vs2%, ventricular arrythmias 9.2%vs5.2%, coronary dissection 58%vs42.7%, and need for mechanical circulatory support 7%vs2.7% respectively. Percutaneous coronary intervention (PCI) was performed among 45.2% patients; however, on coarsened exact matching of baseline characteristics, PCI had no association with mortality, patients (OR 1.22, 95%CI0.69-2.16, p = 0.49). The prevalence of CAA on CA trend towards increased mortality with ACS increased over the years 2012-2018 (linear p-trend <0.05). The 30-day readmissions rate were 13.8% (non-CAA) vs 4.6% (CAA) p = 0.001 predominantly cardiovascular causes (50.9%vs70.7%) and PCI on readmission (7.06%vs17.5%). CAA is an uncommon anomaly noted on coronary angiography. The higher mortality in patients with ACS and increasing trend of CAA-ACS warrants more research.


Non-specific (non-gonococcal) urethritis.
A report is made of a small study of ureaplasmas and chlamydias in 32 cases of non-specific urethritis. Erythromycin was used as a therapeutic agent and found to be reasonably effective.


Modeling the effects of physical activity, education, health, and subjective wealth on happiness based on Indonesian national survey data.
Studies on physical activity's psychological benefits are generally fewer than those on its physiological benefits, and these limited studies have mostly investigated its impact on cognitive functions. Studies exclusively investigating physical activity's effects on happiness are rare. This study aims to investigate the effect of physical activity on psychological functions, especially on happiness. Analysis was based on a large field of nationally representative Indonesian adult data. Data were compiled based on face-to-face interviews with 12,051 adults. Participants provided measures of physical activity, subjective health, and happiness, and responses were recorded with computer-assisted personal interviewing (CAPI) software. Demographic data, including gender, subjective wealth, education, and age, were also included in the analysis. Structural equation modeling (SEM) was conducted to determine the relationship between physical activity, health, subjective wealth, and happiness. The tested model of the association between physical activity, health, subjective wealth, and happiness indicated a good fit, based on χ2 (1, n = 12,051) = 48.733, p = .001, RMSEA = .063, and CFI = .97. Path analysis results showed that health conditions mediated the effects of physical activity on happiness. The result also showed positive effects of education level and subjective wealth on happiness. This study provides evidence that engagement in physical activity has a positive impact on happiness. Indonesian adults should engage in more active lifestyles since more than one-third of Indonesians did not get enough physical activity.


Demonstrating stratification in a European American population.
Population stratification occurs in case-control association studies when allele frequencies differ between cases and controls because of ancestry. Stratification may lead to false positive associations, although this issue remains controversial. Empirical studies have found little evidence of stratification in European-derived populations, but potentially significant levels of stratification could not be ruled out. We studied a European American panel discordant for height, a heritable trait that varies widely across Europe. Genotyping 178 SNPs and applying standard analytical methods yielded no evidence of stratification. But a SNP in the gene LCT that varies widely in frequency across Europe was strongly associated with height (P < 10(-6)). This apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. The failure of standard methods to detect this stratification indicates that new methods may be required.


Splenic rupture as an endoscopic complication: as rare as it appears?
The case was an 86-year-old male with multiple cardiovascular comorbidites, including anticoagulated atrial fibrillation, who underwent a colonoscopy due to acute lower gastrointestinal bleeding and anemia. Colonoscopy only showed some small angiodysplasias in the cecum. A few hours later, the patient presented with abdominal pain and hemodynamic instability. An abdominal computed tomography was performed, which showed a splenic laceration and hemoperitoneum. An expectant attitude was decided, with a good evolution from the abdominal point of view. There was no sign of active splenic bleeding in a control computed tomography. However, he developed decompensated heart failure and finally died.


Mechanobiological considerations in colorectal stapling: Implications for technology development.
Technological advancements in minimally invasive surgery have led to significant improvements in patient outcomes. One such technology is surgical stapling, which has evolved into a key component of many operating rooms by facilitating ease and efficacy in resection and repair of diseased or otherwise compromised tissue. Despite such advancements, adverse post-operative outcomes such as anastomotic leak remain a persistent problem in surgical stapling and its correlates (i.e., hand-sewing), most notably in low colorectal or coloanal procedures. Many factors may drive anastomotic leaks, including tissue perfusion, microbiome composition, and patient factors such as pre-existing disease. Surgical intervention induces complex acute and chronic changes to the mechanical environment of the tissue; however, roles of mechanical forces in post-operative healing remain poorly characterized. It is well known that cells sense and respond to their local mechanical environment and that dysfunction of this "mechanosensing" phenomenon contributes to a myriad of diseases. Mechanosensing has been investigated in wound healing contexts such as dermal incisional and excisional wounds and development of pressure ulcers; however, reports investigating roles of mechanical forces in adverse post-operative gastrointestinal wound healing are lacking. To understand this relationship well, it is critical to understand: 1) the intraoperative material responses of tissue to surgical intervention, and 2) the post-operative mechanobiological response of the tissue to surgically imposed forces. In this review, we summarize the state of the field in each of these contexts while highlighting areas of opportunity for discovery and innovation which can positively impact patient outcomes in minimally invasive surgery.


Psittacosis: diagnosis and management of severe pneumonia and multi organ failure.
Two patients were admitted directly to our Intensive Care Unit in acute respiratory failure due to pneumonia with septicaemic shock, renal and hepatic impairment. Sputum and blood cultures failed to grow any organisms and despite broad spectrum antibiotic therapy for 7 days, neither patient improved. Diagnosis of the rare pneumonic form of psittacosis was made following a raised titre. After treatment with tetracyclines, both patients made a rapid recovery. Retrospective direct questioning revealed that they had close contact with psitacine birds.


[Effect of ether anesthesia on pentosephosphate cycle dehydrogenase activity in different parts of the brain].
Investigations carried out on 19 dogs demonstrated that under ether anesthesia and with the anesthetic concentration in the arterial blood of 126.4 +/- 15.4 mg% the activity of the glucose-6-phosphate and 6-phosphogluconate dehydrogenases in the optic and auditory areas of the brain cortex as well as in the median thalamus experiences no significant changes.


[Epidemiologic situation and measures for prevention of infectious diseases in Sverdlovsk region in 2006-2007].
Materials characterizing the epidemiologic situation on most significant infectious diseases in Sverdlovsk region are presented. Experience on providing the epidemiologic welfare based on systematic surveillance for activity of various factors influencing the epidemic process is described.


Harnessing the power of macrophages/monocytes for enhanced bone tissue engineering.
Bone tissue engineering has attracted considerable attention as a promising treatment modality for severe bone degeneration. The pressing need for more sophisticated and fully functional bone substitutes has spurred a refocus on the development of bone constructs in a way more comparable to the physiological process. Current research is increasingly revealing the central roles of macrophages/monocytes in regulating bone development and repair, so we propose that these immunocytes can play a similar pivotal role in directing engineered bone regeneration. Accordingly, we discuss two possible strategies to exemplify how the distinctive power of macrophages/monocytes--particularly their cytokine-secretion ability and chemotactic response to foreign materials--can be harnessed to enhance the performance of bone tissue engineering applications.


Phytohormone profiles in non-transformed and AtCKX transgenic centaury (Centaurium erythraea Rafn) shoots and roots in response to salinity stress in vitro.
Plant hormones regulate numerous developmental and physiological processes. Abiotic stresses considerably affect production and distribution of phytohormones as the stress signal triggers. The homeostasis of plant hormones is controlled by their de novo synthesis and catabolism. The aim of this work was to analyse the contents of total and individual groups of endogenous cytokinins (CKs) as well as indole-3-acetic acid (IAA) in AtCKX overexpressing centaury plants grown in vitro on graded NaCl concentrations (0, 50, 100, 150, 200 mM). The levels of endogenous stress hormones including abscisic acid (ABA), salicylic acid (SA) and jasmonic acid (JA) were also detected. The elevated contents of total CKs were found in all analysed centaury shoots. Furthermore, increased amounts of all five CK groups, as well as enhanced total CKs were revealed on graded NaCl concentrations in non-transformed and AtCKX roots. All analysed AtCKX centaury lines exhibited decreased amounts of endogenous IAA in shoots and roots. Consequently, the IAA/bioactive CK forms ratios showed a significant variation in the shoots and roots of all AtCKX lines. In shoots and roots of both non-transformed and AtCKX transgenic centaury plants, salinity was associated with an increase of ABA and JA and a decrease of SA content.


Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.
In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients.


The multipotential cells of the limbus.
Ample evidence exists that there is a centripetal movement of cells from the periphery of the cornea toward the centre. While conjunctival cells have the capacity to transdifferentiate into corneal epithelial cells, the limbal region appears to act as a barrier between the conjunctival and corneal epithelia, even after large epithelial defects are created. The existence of limbal stem cells is suggested by the apparent role of the limbus in acting as a source of peripheral corneal cells. While specific staining of limbal cells has been reported in the rabbit, there is no positive identification of such stem cells in the human. However, in the human there is negative staining for both a keratin cytoskeleton antigen and a cell surface antigen in the limbal epithelial zone. Efforts positively to identify human limbal stem cells continue, as do efforts to culture and transplant such cells.


High thoracic/cervical epidural blood patch for spontaneous cerebrospinal fluid leak: a new challenge for anesthesiologists.
Spontaneous cerebral spinal fluid leakage is increasingly recognized as a cause of headache due to low intracranial pressure. The site of leakage can be identified with radionuclide cisternography, and anesthesiologists are increasingly requested to provide epidural blood patch for their management. This series of case reports demonstrates some of the issues relating to the management of this condition.


Synergistic Effects of Gold Nanocages in Hyperthermia and Radiotherapy Treatment.
Gold nanocages (GNCs) are a promising material that not only converts near infrared (NIR) light to heat for the ablation of tumors but also acts as a radiosensitizer. The combination of hyperthermia and radiotherapy has a synergistic effect that can lead to significant tumor cell necrosis. In the current study, we synthesized GNCs that offered the combined effects of hyperthermia and radiotherapy. This combination strategy resulted in increased tumor cell apoptosis and significant tumor tissue necrosis. We propose that GNCs can be used for clinical treatment and to potentially overcome resistance to radiotherapy by clearly increasing the antitumor effect.


Potential consumer exposure to respirable particles and TiO2 due to the use of eyebrow powders.
Cosmetic powders contain numerous components, including titanium dioxide (TiO2), which is classified as possibly carcinogenic to humans (Group 2B). However, little is known about potential inhalation exposures to particles that are released during cosmetic powder applications. We realistically simulated the application of five different eyebrow powders using a mannequin and then determined concentrations of total suspended particles (TSP), PM10, and PM4 fractions of particles that would be inhaled during powder application. We determined the size and shape of particles in the original powders and released particles, as well as their TiO2 concentrations and Ti content of individual particles. The application of eyebrow powders resulted in the release and inhalation of airborne particles at concentrations ranging from 21.2 to 277.3 µg/m3, depending on the particle fraction and the powder. The concentrations of TiO2 in PM4 and PM10 samples reached 2.7 µg/m3 and 9.3 µg/m3, respectively. The concentration of TiO2 in airborne particle fractions was proportional to the presence of TiO2 in the bulk powder. The application of eyebrow powders results in user exposures to respirable PM4 and PM10 particles, including those containing TiO2. This information should be of interest to stakeholders concerned about inhalation exposure to TiO2.


Observation of NMR noise from solid samples.
We demonstrate that proton NMR noise signals, i.e. NMR spectra without excitation by radio frequency, can be obtained from solid samples. Experimental results are shown for static and magic-angle spinning conditions. In addition, a tuning procedure based on the probes' NMR noise characteristics and similar to the one described previously for liquids probes can also be used to optimize signal-to-noise ratios in ¹H-MAS experiments.


In vivo performance evaluation of the Achilles Insight QUS device.
Achilles plus (GE, Lunar) has been widely used worldwide for more than a decade, and for its precision, ability to predict fragility fractures and comparability to central DXA, it can be considered a reference standard among quantitative ultrasound devices. As a water-bath system, Achilles plus has obvious practical drawbacks. Achilles Insight is a new-generation device that gives ultrasound parameters in less than 1 min, providing real-time imaging of the os calcis. The aim of this study was to evaluate the in vivo performance of Achilles Insight in comparison to Achilles plus. The precision showed a coefficient of variation (CV) of 0.5 and 0.4%, 4.1 and 3.0%, 2.7 and 2.1%, respectively, for speed of sound (SOS), broadband ultrasound attenuation (BUA), and Stiffness obtained with Achilles plus and Achilles Insight. We also studied 117 postmenopausal women (mean age: 67.1+/-8.8 yr), 47 with and 70 without fragility fractures. Ultrasound parameters obtained by the two devices significantly (p<0.001) correlated and resulted in agreement according to the Bland and Altman method. Achilles plus and Achilles Insight showed similar values of areas under receiver operating characteristics (ROC) curves in discriminating patients with or without fractures (0.884, 0.82, and 0.879 for SOS, BUA, and Stiffness, respectively, with Achilles plus, and 0.882, 0.828, and 0.889, respectively, for Achilles Insight). In conclusion, the better precision of the Achilles Insight with respect to Achilles plus could be explained by the fact that the measurement with Achilles Insight needs less time and gives a consequent reduction in motion artifacts. The high correlation and the similar ability to identify postmenopausal women with vertebral fracture suggest the possibility of using the database of Achilles plus for Achilles Insight.


Determination of gag and env subtypes of HIV-1 detected among injecting drug users (IDUs) in Manipur, India: evidence for intersubtype recombination.
The majority of HIV-1 transmission in Manipur, one of the northeastern states of India, is through the sharing of needles and syringes among the injecting drug users (IDUs). A total of 28 HIV seropositive samples were used to determine the HIV-1 subtypes with respect to both gag and envelope genes. The specific regions within gag and envelope genes were amplified from PBMC DNA by nested PCR using appropriate primers. These amplicons were used in heteroduplex mobility assay followed by DNA sequencing. Phylogenetic analysis of the nucleotide sequences of respective regions showed that 89% of samples (25/28) were infected with subtype C with respect to both gag and envelope genes; however, 11% of the samples (3/28) showed subtype discordance with respect to the envelope (C2-V3) and gag (p24-p7) genomic regions. Simplot analysis of the discordant samples showed the presence of intersubtype recombination between subtype C and Thai B; two samples were found to be subtype C in envelope but Thai B in gag, whereas, one sample was found to be subtype Thai B in envelope and 'C' in gag region.


What do we mean by long COVID? A scoping review of the cognitive sequelae of SARS-CoV-2 infection.
Many COVID-19 patients report persistent symptoms, including cognitive disturbances. We performed a scoping review on this topic, focusing primarily on cognitive manifestations. Abstracts and full texts of studies published on PubMed (until May 2023) addressing cognitive involvement persisting after SARS-CoV-2 infection were reviewed, focusing on terms used to name the cognitive syndrome, reported symptoms, their onset time and duration, and testing batteries employed. Reported psychiatric symptoms, their assessment tools, and more general manifestations were also extracted. Among the 947 records identified, 180 studies were included. Only one third of them used a label to define the syndrome. A minority of studies included patients according to stringent temporal criteria of syndrome onset (34%), whereas more studies reported a minimum required symptom duration (77%). The most frequently reported cognitive symptoms were memory and attentional-executive disturbances, and among psychiatric complaints, the most frequent were anxiety symptoms, depression, and sleep disturbances. Most studies reported fatigue among general symptoms. Thirty-six studies employed cognitive measures: screening tests alone (n = 19), full neuropsychological batteries (n = 25), or both (n = 29); 30 studies performed psychiatric testing. Cognitive deficits were demonstrated in 39% of subjects, the most frequently affected domains being attention/executive functions (90%) and memory (67%). Currently, no agreement exists on a label for post-COVID-19 cognitive syndrome. The time of symptom onset after acute infection and symptom duration are still discussed. Memory and attention-executive complaints and deficits, together with fatigue, anxiety, and depression symptoms, are consistently reported, but the objective evaluation of these symptoms is not standardized.


The Changing Epidemiology of Candidemia in the United States: Injection Drug Use as an Increasingly Common Risk Factor-Active Surveillance in Selected Sites, United States, 2014-2017.
Injection drug use (IDU) is a known, but infrequent risk factor on candidemia; however, the opioid epidemic and increases in IDU may be changing the epidemiology of candidemia. Active population-based surveillance for candidemia was conducted in selected US counties. Cases of candidemia were categorized as IDU cases if IDU was indicated in the medical records in the 12 months prior to the date of initial culture. During 2017, 1191 candidemia cases were identified in patients aged >12 years (incidence: 6.9 per 100 000 population); 128 (10.7%) had IDU history, and this proportion was especially high (34.6%) in patients with candidemia aged 19-44. Patients with candidemia and IDU history were younger than those without (median age, 35 vs 63 years; P < .001). Candidemia cases involving recent IDU were less likely to have typical risk factors including malignancy (7.0% vs 29.4%; relative risk [RR], 0.2 [95% confidence interval {CI}, .1-.5]), abdominal surgery (3.9% vs 17.5%; RR, 0.2 [95% CI, .09-.5]), and total parenteral nutrition (3.9% vs 22.5%; RR, 0.2 [95% CI, .07-.4]). Candidemia cases with IDU occurred more commonly in smokers (68.8% vs 18.5%; RR, 3.7 [95% CI, 3.1-4.4]), those with hepatitis C (54.7% vs 6.4%; RR, 8.5 [95% CI, 6.5-11.3]), and in people who were homeless (13.3% vs 0.8%; RR, 15.7 [95% CI, 7.1-34.5]). Clinicians should consider injection drug use as a risk factor in patients with candidemia who lack typical candidemia risk factors, especially in those with who are 19-44 years of age and have community-associated candidemia.


[The use of venous catheter : Which ones to choose, how to prevent their complications?]
Intravenous catheters are multiple and essential for daily practice. They are also responsible for high morbidity and mortality. Simple or echo-guided peripheral venous catheters, midlines, PICCline, tunneled or non-tunneled central venous catheters, and implantable venous access device are currently at our disposal. Thus, catheter selection, duration and indications for use, and prevention and treatment of complications vary according to the situation. The objective of this update is to provide the clinician with an overview of knowledge and rules of good practice on the use of catheters.


Bleeding Events After Image-Guided Breast Biopsies: Comparison of Patients Temporarily Discontinuing Versus Maintaining Antithrombotic Therapy During Biopsy.
BACKGROUND. Antithrombic (AT) therapy is commonly temporarily discontinued before breast core needle biopsy (CNB), introducing risks of thrombotic events and diagnostic delay. OBJECTIVE. The purpose of this article was to compare the frequency of postbiopsy bleeding events among patients without AT use, patients temporarily discontinuing AT therapy, and patients maintaining AT therapy during breast CNB. METHODS. This retrospective study included 5302 patients (median age, 52 years) who underwent image-guided breast or axillary CNB between January 1, 2014, and December 31, 2019. From January 1, 2014, to December 31, 2016, patients temporarily discontinued all AT therapy for 5 days before CNB; from January 1, 2017, to December 31, 2019, patients maintained AT therapy during CNB. Immediate postbiopsy mammograms were reviewed for imaging-apparent hematoma. Patients were called 24-48 hours after biopsy and asked regarding palpable hematoma and breast bruise. The EMR was reviewed for clinically significant postbiopsy hematoma (i.e., hematoma requiring drainage, primary care or emergency department visit for persistent symptoms, or hospital admission). Bleeding events were compared among groups, including Firth bias-reduced multivariable logistic regression analysis. RESULTS. During CNB, 4665 patients were not receiving AT therapy, 423 temporarily discontinued AT therapy, and 214 maintained AT therapy. Imaging-apparent hematoma occurred in 3% of patients without AT use, 6% of patients discontinuing AT therapy, and 7% of patients maintaining AT therapy (p = .60 [discontinuing vs maintaining]). Palpable hematoma occurred in 2% of patients without AT use, 4% of patients maintaining AT therapy, and 4% of patients discontinuing AT therapy (p = .92 [discontinuing vs maintaining]). Breast bruise occurred in 2% of patients without AT use, 1% of patients discontinuing AT therapy, and 6% of patients maintaining AT therapy (p < .001 [discontinuing vs maintaining]). In multivariable analysis adjusting for age, biopsy imaging modality, needle gauge, number of biopsy samples, and pathologic result, discontinued AT therapy (using maintained AT therapy as reference) was not a significant independent predictor of imaging-apparent hematoma (p = .23) or palpable hematoma (p = .91) but independently predicted decreased risk of bruise (OR = 0.11, p < .001). No patient developed clinically significant postbiopsy hematoma. CONCLUSION. Frequencies of imaging-apparent and palpable hematoma were not significantly different between patients temporarily discontinuing versus maintaining AT therapy. CLINICAL IMPACT. The findings support the safety of continuing AT therapy during CNB. Patients who maintain AT therapy should be counseled regarding risk of bruise.


The prevalence of canine dirofilariasis in China: a systematic review and meta-analysis.
Dirofilariasis, the disease caused by Dirofilaria spp., and in particular by Dirofilaria immitis and Dirofilaria repens in canines, occurs frequently in canids and felids, and occasionally in humans, in temperate, sub-tropical and tropical regions globally. Although highly effective, safe and convenient preventive medicines have been available for the treatment of dirofilariasis for the past three decades, the disease remains a major veterinary and public health concern in endemic areas. The insect vectors, host-parasite relationships and interactions of Dirofilaria spp. have received little attention in China, and there is very little information in English regarding the prevalence of dirofilariasis in animals and humans in the country. The aim of this systematic review and meta-analysis is to evaluate the status of canine dirofilariasis in China based on the available literature in English and in Chinese. We systematically searched five databases for epidemiologic studies on the prevalence of canine dirofilariasis in China and finally selected 42 studies eligible for inclusion in the systematic review and meta-analysis. The meta-analysis was performed using the random effects model in the meta package in R v4.2.1. The random effects model gave a pooled and weighted prevalence of Dirofilaria infection among dogs in China in the past 100 years of 13.8% (2896/51,313, 95% confidence interval 8.2-20.4%) with a high level of heterogeneity (I2 = 99.5%). Our analyses indicated that the prevalence of canine dirofilariasis in China has gradually declined, but that the range of Dirofilaria spp. has expanded. Older and outdoor dogs presented a higher rate of positive infection. The findings indicated that more attention should be paid to host factors for the effective control and management of this disease.


A case of pyoderma gangrenosum around the urethral meatus aggravated by COVID-19 infection and further worsened due to the development of pyogenic osteomyelitis 8 years after urostomy.
After the infection with COVID-19, pyoderma gangrenosum worsened and further led to necrosis following pyogenic osteomyelitis. Infection is a major exacerbating factor in pyoderma gangrenosum.


Celiac disease: experience of general practitioners in Brianza Area- Monza- Milan-Italy.
The purpose of the study was to better investigate the degree of knowledge and the diagnostic approach concerning celiac disease and its extra-intestinal manifestations by general practitioners in Italy. Celiac Disease is a common chronic disease, but often goes undiagnosed because of atypical symptoms or silent disease. Currently there are non-definitive data about the disease management approach concerning celiac disease by general practitioners. To better investigate the degree of knowledge and the diagnostic approach concerning celiac disease and its extra-intestinal manifestations, questionnaire was used to assess the daily practice of diagnosis, treatment, and follow-up of this condition by general practitioners in two densely populated area in Italy: Monza-Brianza Area and Milan City. The questionnaire was composed of 18 questions that explored 3 precise domains: diagnosis criteria, correct management of celiac disease and availability for training. The frequencies of the domains explored were analyzed, analyzes were carried out to identify differences between the groups of general practitioners interviewed. Analysis of the questionnaires showed a degree of knowledge and preparation comparable to that of other countries, even though not sufficient to guarantee access to early diagnosis for all patients with celiac disease. The knowledge was not influenced by the years of experience or specific curriculum of health professionals. General practitioners under 40 were much more in favor of continuous training and were aware of its importance (OR=10.55; CI95%: 1.62-445.39), although this need was a high priority in the whole group interviewed (84.7%). Continuous specific training aimed at primary care physicians and general practitioners is the first tool to improve early diagnosis. A second opportunity is represented by the continuous dialogue between general practitioners and tertiary level hospitals and universities.


Comparison of enzyme immunoassay and dextran-coated charcoal techniques for progesterone receptor determination in human breast cancer cytosols.
We have compared a new enzyme immunoassay for progesterone receptors (Abbott PgR-EIA, monoclonal) with our standard radioligand binding-assay (PgR-RBA). For both assays cytosols were freshly prepared from human breast cancer specimens that had been stored frozen for up to 1 year, and predominantly tissues were used which contained critically low amounts of progesterone receptors. A highly significant correlation was observed between the PgR-EIA and PgR-RBA (Spearman: Rs = 0.85, n = 100). Using a cut-off point of 10 fmol PgR/mg protein, 87% of the values were in accordance with each other (52% negative, and 35% positive in both assays), whereas 13% scored positive (median: 16, range 11-38 fmol PgR/mg protein) in one assay and negative (median: 7, range 0-10 fmol PgR/mg protein) in the other. Also in cytosols from human ovarian and endometrial carcinoma tissues immunoreactive PgR could be detected, and significant correlations with PgR-RBA were observed (Rs = 0.94, n = 6) for both tissues.


Association between species-specific staphylococcal intramammary infections and milk somatic cell score over time in dairy goats.
Numerous factors affect milk somatic cell score (SCS) in dairy goats including physiologic factors such as stage of lactation, and pathological factors such as bacterial intramammary infection (IMI), e.g. staphylococcal IMI. The association between IMI and udder inflammation and especially differences in the inflammatory response between the different staphylococcal species are yet to be identified. The objectives of this study were to use data from a recently published longitudinal study that characterized IMI status over time to evaluate the species-specific effect of staphylococcal IMI on udder half-level milk SCS, and to evaluate the effect of time since IMI diagnosis on this relationship. Half-level milk samples for culture and determination of SCS were collected from 171 goats starting within 10 days in milk (DIM), and then at various intervals until ≥ 120 DIM. A mixed linear model was used to assess the effect of species-specific staphylococcal IMI on SCS, accounting for confounding by lentivirus infection, parity, DIM, and the contralateral half IMI status, and for repeated measurements within udder half and for clustering of halves within goat. A second model was used to evaluate the effect of time since first IMI diagnosis and its interaction with staphylococcal IMI status on the relationship between staphylococcal IMI status and SCS. Lentivirus seropositivity and contralateral half IMI status were associated with SCS. Staphylococcal IMI status was associated with SCS, with differences between species. Staphyloccocus caprae, Staphylococcus epidermidis, Staphylococcus simulans, and Staphylococcus xylosus were associated with higher SCS than a number of other species. Time since first diagnosis did not modify the relationship between IMI status and SCS.