Anticholinergics for asthma: a long history.
To provide a fast overview about the introduction and development of anticholinergic drugs in Western medicine to their current indications particularly in asthma. Although short-acting muscarinic antagonists have been positioned in the last 15 years for the treatment of adults and children with moderate-to-severe acute asthma in the emergency setting (reducing the risk of hospital admissions and improving lung function), a growing body of evidence has recently emerged that positions the long-acting muscarinic anticholinergic tiotropium bromide as add-on therapy to at least inhaled corticosteroids (ICS) maintenance therapy in adults, adolescents, and children with symptomatic asthma. Thus, the addition of tiotropium bromide to ICS alone or ICS and another controller was associated with significant improvements in spirometric measures and asthma control, and a significantly decrease in the rate of asthma exacerbations. Short-acting muscarinic antagonists and tiotropium bromide have a well established role in the treatment of different phases of asthma. Further data are needed to provide more evidence on other selective long-acting muscarinic antagonists in addition to tiotropium as potential treatment options.


The value of duplicate slides on atypical squamous cells, cannot exclude high-grade intraepithelial lesion.
Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) category was added to the 2001 Bethesda System. ASC-H accounts for a small percentage (0.2-0.6%) of abnormal Pap smears and includes heterogenous group of lesions. There are more high-grade cervical lesions (30-50%) in ASC-H than ASC-US (10-15%). An accurate Pap diagnosis is crucial for appropriate patient follow-up and treatment. A total of 43 consecutive ASC-H cases were collected from October 2007 to March 2008, and all duplicate and the original slides were reviewed blindly at the end of the study. On review of the duplicate Pap slides, 18 cases had diagnostic SIL cells (15 HSIL, 2 LSIL with ASC-H, and 1 LSIL). The duplicate slides could have potentially changed 18 (41.9%) ASC-H diagnoses to a more definitive SIL diagnosis. On review of the original Pap slides, 8 of these 18 cases also had HSIL cells. Twenty-one follow-up cervical biopsies (21/43, 48.8%) showed 12 CIN 2/3, 4 CIN 1, 1 VAIN 1, 2 cervical polyps, 1 negative for dysplasia, and 1 insufficient for diagnosis. The CIN 2/3 rate was 57.1% (12/21) based on the original ASC-H Pap diagnosis. The CIN 2/3 rates were 80% (8/10) with SIL cells on duplicate slides and 36.4% (4/11) without SIL cases on duplicate slides. Our study suggested that duplicate slides were very useful for further classification of ASC-H, but other ancillary tests might be necessary for some cases. We propose a systematic approach using combined duplicate slides and reflex HPV testing to further classify ASC-H.


Dietary polyphenols in prevention and treatment of prostate cancer.
Prostate cancer is the most prevalent disease affecting males in many Western countries, with an estimated 29,480 deaths in 2014 in the US alone. Incidence rates for prostate cancer deaths have been decreasing since the early 1990s in men of all races/ethnicities, though they remain about 60% higher in African Americans than in any other group. The relationship between dietary polyphenols and the prevention of prostate cancer has been examined previously. Although results are sometimes inconsistent and variable, there is a general agreement that polyphenols hold great promise for the future management of prostate cancer. Various dietary components, including polyphenols, have been shown to possess anti-cancer properties. Generally considered as non-toxic, dietary polyphenols act as key modulators of signaling pathways and are therefore considered ideal chemopreventive agents. Besides possessing various anti-tumor properties, dietary polyphenols also contribute to epigenetic changes associated with the fate of cancer cells and have emerged as potential drugs for therapeutic intervention. Polyphenols have also been shown to affect post-translational modifications and microRNA expressions. This article provides a systematic review of the health benefits of selected dietary polyphenols in prostate cancer, especially focusing on the subclasses of polyphenols, which have a great effect on disease prevention and treatment.


Treatment of complications associated with systemic sclerosis.
Current and emerging drug therapy options for patients suffering from the complications of systemic sclerosis are presented. Systemic sclerosis is a devastating and rare, chronic, autoimmune disease and is characterized by various disease complications due to skin thickening, vascular damage, and inflammation affecting numerous organs. There are two major subtypes of systemic sclerosis: limited cutaneous scleroderma and diffuse cutaneous scleroderma. Patients suffer from Raynaud's phenomenon, skin changes, musculoskeletal changes, gastrointestinal complications, pulmonary complications, scleroderma renal crisis, and dryness of the eyes and mouth. Currently, there is no cure for systemic sclerosis, but research is focusing on decreasing the progression and symptoms of this disease. Raynaud's phenomenon is the temporary vasoconstriction of the small vessels of the fingers, toes, tip of the nose, and earlobes. Skin thickening is the cardinal symptom of systemic sclerosis, with as many as 50% of patients developing digital ulcers. Care of these ulcers is crucial in the prevention of osteomyelitis and other infections. Malabsorption syndrome may also occur in patients, many of whom will eventually require parenteral nutrition to maintain their caloric needs. Pulmonary interstitial fibrosis and pulmonary arterial hypertension are additional serious complications of systemic sclerosis. The use of prostacyclin analogues, phosphodiesterase inhibitors, calcium-channel blockers, cyclophosphamide, bosentan, and other agents has been investigated in patients suffering from the complications of systemic sclerosis. Systemic sclerosis is characterized by various circulatory, dermatological, gastrointestinal, musculoskeletal, pulmonary, and renal complications. Although there is no cure for systemic sclerosis, management of its associated complications can help improve patients' quality of life.


A chromosomally located transposon in Pseudomonas aeruginosa.
A new transposon, Tn2521, coding for carbenicillin, streptomycin, spectinomycin, and sulfanilamide resistance, has been identified in Pseudomonas aeruginosa. The transposon occurs naturally in the chromosome of clinical strains of P. aeruginosa isolated in geographically separated hospitals. This has been demonstrated by its transductional linkage to the pur-136 marker and also by Southern hybridization. Tn2521 is 6.8 kilobases, can transpose from the chromosome to both IncP-1 and IncP-2 plasmid genomes, and has a pattern of restriction endonuclease sites unlike that of any previously described transposon. The carbenicillin resistance carried by Tn2521 is due to the PSE-4 type of beta-lactamase.


Automated image registration: II. Intersubject validation of linear and nonlinear models.
Our goal was to validate linear and nonlinear intersubject image registration using an automated method (AIR 3.0) based on voxel intensity. PET and MRI data from 22 normal subjects were registered to corresponding averaged PET or MRI brain atlases using several specific linear and nonlinear spatial transformation models with an automated algorithm. Validation was based on anatomically defined landmarks. Automated registration produced results that were superior to a manual nine parameter variant of the Talairach registration method. Increasing the degrees of freedom in the spatial transformation model improved the accuracy of automated intersubject registration. Linear or nonlinear automated intersubject registration based on voxel intensities is computationally practical and produces more accurate alignment of homologous landmarks than manual nine parameter Talairach registration. Nonlinear models provide better registration than linear models but are slower.


Towards an understanding of the burdens of medication management affecting older people: the MEMORABLE realist synthesis.
More older people are living in the community with multiple diagnoses and medications. Managing multiple medications produces issues of unrivalled complexity for those involved. Despite increasing literature on the subject, gaps remain in understanding how, why and for whom complex medication management works, and therefore how best to improve practice and outcomes. MEMORABLE, MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation, aimed to address these gaps. MEMORABLE used realism to understand causal paths within medication management. Informed by RAMESES (Realist And Meta-narrative Evidence Synthesis: and Evolving Standards) guidelines, MEMORABLE involved three overlapping work packages: 1) Realist Review of the literature (24 articles on medication management exploring causality); 2) Realist Evaluation (50 realist-informed interviews with older people, family carers and health and care practitioners, explaining their experiences); and 3) data synthesis and theorising from 1) and 2). Medication management was viewed from the perspective of 'implementation' and structured into five stages: identifying a problem (Stage 1), getting a diagnosis and/or medications (Stage 2), starting, changing or stopping medications (Stage 3), continuing to take medications (Stage 4), and reviewing/reconciling medications (Stage 5). Three individual stages (1, 3 and 4) are conducted by the older person sometimes with family carer support when they balance routines, coping and risk. Stages 2 and 5 are interpersonal where the older person works with a practitioner-prescriber-reviewer, perhaps with carer involvement. Applying Normalisation Process Theory, four steps were identified within each stage: 1) sense making: information, clarification; 2) action: shared-decision-making; 3) reflection/monitoring; and 4) enduring relationships, based on collaboration and mutual trust. In a detailed analysis of Stage 5: Reviewing/reconciling medications, adopting the lens of 'burden', MEMORABLE identified five burdens amenable to mitigation: ambiguity, concealment, unfamiliarity, fragmentation and exclusion. Two initial improvement propositions were identified for further research: a risk screening tool and individualised information. Older people and family carers often find medication management challenging and burdensome particularly for complex regimens. Practitioners need to be aware of this potential challenge, and work with older people and their carers to minimise the burden associated with medication management. PROSPERO 2016:CRD42016043506.


A genetic model for understanding higher order visual processing: functional interactions of the ventral visual stream in Williams syndrome.
Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a 1.6 Mb microdeletion on chromosome 7q11.23 and characterized by hypersocial personality and prominent visuospatial construction impairments. Previous WS studies have identified functional and structural abnormalities in the hippocampal formation, prefrontal regions crucial for amygdala regulation and social cognition, and the dorsal visual stream, notably the intraparietal sulcus (IPS). Although aberrant ventral stream activation has not been found in WS, object-related visual information that is processed in the ventral stream is a critical source of input into these abnormal regions. The present study, therefore, examined neural interactions of ventral stream areas in WS. Using a passive face- and house-viewing paradigm, activation and functional connectivity of stimulus-selective regions in fusiform and parahippocampal gyri, respectively, were investigated. During house viewing, significant activation differences were observed between participants with WS and a matched control group in IPS. Abnormal functional connectivity was found between parahippocampal gyrus and parietal cortex and between fusiform gyrus and a network of brain regions including amygdala and portions of prefrontal cortex. These results indicate that abnormal upstream visual object processing may contribute to the complex cognitive/behavioral phenotype in WS and provide a systems-level characterization of genetically mediated abnormalities of neural interactions.


Optimal Gabor filters for texture segmentation.
Texture segmentation involves subdividing an image into differently textured regions. Many texture segmentation schemes are based on a filter-bank model, where the filters, called Gabor filters, are derived from Gabor elementary functions. The goal is to transform texture differences into detectable filter-output discontinuities at texture boundaries. By locating these discontinuities, one can segment the image into differently textured regions. Distinct discontinuities occur, however, only if the Gabor filter parameters are suitably chosen. Some previous analysis has shown how to design filters for discriminating simple textures. Designing filters for more general natural textures, though, has largely been done ad hoc. We have devised a more rigorously based method for designing Gabor filters. It assumes that an image contains two different textures and that prototype samples of the textures are given a priori. We argue that Gabor filter outputs can be modeled as Rician random variables (often approximated well as Gaussian rv's) and develop a decision-theoretic algorithm for selecting optimal filter parameters. To improve segmentations for difficult texture pairs, we also propose a multiple-filter segmentation scheme, motivated by the Rician model. Experimental results indicate that our method is superior to previous methods in providing useful Gabor filters for a wide range of texture pairs.


[Langerhans cell histiocytosis: petrosal remodelling after chemotherapy--case report and review of the literature].
We report the case of a child presented by her parents to the ENT outpatient service for swelling of the right temporal bone. The child had a history of recurrent bilateral inflammation of the middle ear. Tympanometry revealed a reduced compliance. Due to conductive hearing loss it was impossible to measure otoacustic emissions. Otherwise a normal ENT status was found. Imaging (MRI/CT) demonstrated bitemporal soft-tissue changes with extensive osseous destruction, but no typical imaging signs of an inflammatory, dysplastic or expansive process. The tentative diagnosis of Langerhans' cell histiocytosis (LCH) made on the basis of the clinical and imaging findings was confirmed by biopsy. After exclusion of disseminated LCH, chemotherapy was initiated, and the child underwent follow-up imaging after 3 months. CT showed clear signs of bitemporal reossification. The case reported here illustrates the problems encountered in diagnosing LCH which may present with unspecific clinical symptoms despite advanced osseous destruction. ENT specialists should be familiar with this very heterogeneous entity and think of LCH especially in children presenting with therapy-refractory otitis media, otitis externa, or mastoiditis in order to ensure a timely diagnosis and to thus improve the chances of successful therapy. Imaging modalities (CT, MRI) have a role in the early diagnosis and follow-up of this disorder.


Familiar music as an enhancer of self-consciousness in patients with Alzheimer's disease.
The main objective of this paper is to examine the impact of familiar music on self-consciousness (SC) in patients with Alzheimer's disease (AD). For this purpose, two AD groups of 20 patients matched by age, educational level, gender, illness duration, and cognitive state were assessed using an SC questionnaire before and after music intervention. The SC questionnaire measured several aspects: personal identity, anosognosia, affective state, body representation, prospective memory, introspection and moral judgments. One AD group received familiar music stimulation and another AD group unfamiliar music stimulation over three months. The AD patients who received a familiar music intervention showed a stabilization or improvement in aspects of SC. By contrast, control AD group showed a deterioration of most of the SC aspects after unfamiliar music stimulation, except the SC aspects of body representation and affective state. Familiar music stimulation could be considered as an enhancer of SC in patients with Alzheimer's disease.


BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms.
The tumour suppressor BRCA1-associated protein 1 (BAP1) is the most frequently mutated cancer gene in mesothelioma. Here we report novel functions for BAP1 in mitotic progression highlighting the relationship between BAP1 and control of genome stability in mesothelioma cells with therapeutic implications. Depletion of BAP1 protein induced proteasome-mediated degradation of BRCA1 in mesothelioma cells while loss of BAP1 correlated with BRCA1 loss in mesothelioma patient tumour samples. BAP1 loss also led to mitotic defects that phenocopied the loss of BRCA1 including spindle assembly checkpoint failure, centrosome amplification and chromosome segregation errors. However, loss of BAP1 also led to additional mitotic changes that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced growth of astral microtubules. Intriguingly, these consequences could be explained by loss of expression of the KIF18A and KIF18B kinesin motors that occurred upon depletion of BAP1 but not BRCA1, as spindle and astral microtubule defects were rescued by re-expression of KIF18A and KIF18B, respectively. We therefore propose that BAP1 inactivation causes mitotic defects through BRCA1-dependent and independent mechanisms revealing novel routes by which mesothelioma cells lacking BAP1 may acquire genome instability and exhibit altered responses to microtubule-targeted agents.


Intra-individual variability of self-esteem in adolescents with spina bifida.
The purpose of this study was to explore intra-individual variability of global self-esteem and physical self-worth in adolescents with spina bifida (n = 3). Three adolescents were assessed in their schools by auto-evaluation over a period of 12 weeks (three times a week) with the Physical Self Inventory-6, a six-item questionnaire with a visual analogue scale. Statistical analyses included auto-correlation function (ACF) for studying the time series. Descriptive statistics demonstrated that in all the dimensions of physical self and global self-esteem, participants showed great variability over time. Auto-correlation function indicated 20 non-stationary and unstable time series, and four stationary time series. The non-stationary evolution of physical self, and global self-esteem in the three adolescents with spina bifida studied may explain the absence of consensus in the literature on the level of the self-perception. Future longitudinal research needs to be engaged.


Effects of sodium and chloride on potassium transport by the bullfrog kidney.
We have studied the effect on K transport of reductions in the Na and Cl concentrations of solutions perfusing the isolated bullfrog kidney. We used recently developed techniques for estimating the unidirectional reabsorptive and secretory K fluxes. Reduction of Na and Cl concentrations in the arterial perfusate from 112 and 100 mM to 22 and 10 mM, respectively, inhibited K secretion 82% and K reabsorption 97%. Reduction of only the Na concentration inhibited K secretion 42% but did not affect K reabsorption. Arterial and portal perfusion with 37 mM Na, 23 mM Cl reduced urine Na concentration to 6 mM and Na reabsorption by 59%. However, K secretion rose 88% and reabsorption fell 76%. Arterial and portal perfusates with 37 mM Na, 100 mM Cl reduced urine Na concentration to 2 mM and Na reabsorption by 46%. Still, K secretion was elevated 57% by an increase in urine flow rate. K reabsorption was not reduced. Arterial and portal perfusates with 112 mM Na, 23 mM Cl, and containing SO4 also stimulated K secretion 26% and inhibited K reabsorption 91%. Thus, reduction of perfusate Na concentration to 22 mM inhibited secretion but 37 mM was sufficient to permit stimulation of secretion by low Cl concentrations and by increased tubular fluid flow rate. Reduction of the perfusate Cl concentration stimulated secretion and inhibited reabsorption. We conclude that a minimum level of Na reabsorption is required to maintain K secretion, but above that minimum level changes in the rate of Na reabsorption do not affect the rate of K secretion. The tubular fluid Cl concentration or the rate of Cl reabsorption affects both reabsorption and secretion of K and, therefore, may be an important regulator of the rate of K excretion.


Data on pilot assessment of efficacy of artemether lumefantrine when co-administered with ciprofloxacin in malaria-typhoid co-infected patients.
Malaria -typhoid co-infection is associated with poverty and underdevelopment with significant morbidity and mortality with similarities in clinical features of the two diseases that often result in misdiagnosis and mistreatment of the febrile patients. The Co-administration of artemether lumefantrine (AL) with ciprofloxacin as treatment for malaria-typhoid co-infection is common in Nigeria and this increases risk of pharmacokinetic drug-drug interaction since ciprofloxacin is an inhibitor of CYP3A4 that metabolizes AL. In an open-label prospective three arm design with registration pactr201909811770922, one hundred and nineteen (119) febrile volunteers comprising 55 males and 64 females were distributed into three oral treatment regimen groups. Group 1 consist of sixty-five participants presenting malaria mono infection treated with AL only and fifty-four participants presenting malaria-typhoid co-infection randomly assigned to Group 2 treated with AL and ciprofloxacin concomitantly and Group 3 whose doses were staggered at 2 hours interval. Blood samples were collected from participants in the three groups on 3 different days: day 0 (before commencement of treatment); day 3 (after completion of AL); and day 7 (after completion of ciprofloxacin), The collected blood sample were used to determine parasite density, serum liver and kidney function parameters, haematological indices, and day 7 lumefantrine concentration. The data in this article provides the changes in PCR-uncorrected Early Treatment Failure (ETA), Late Clinical Failure (LCF), Late Parasitological Failure (LPF), Day 7 serum lumefantrine concentration, liver and kidney function parameters, axillary body temperature and PCV/Hb associated with the different treatment regimen. The dataset [1] as a baseline, will stimulate the need for a randomized clinical assessment of the efficacy of AL when co-administered with ciprofloxacin in the treatment regimen of Malaria-typhoid co-infection in endemic areas. Such findings are capable of influencing national treatment policy on the management of malaria-typhoid co-infection.


The Zurich Study. XXIV. Structural and emotional aspects of childhood and later psychopathology.
A Swiss cohort interviewed four times between ages 20 and 30 years reported on a structural aspect of childhood (separation from parents) and emotional aspects (family strain, childhood behavioral and emotional problems). These data were connected with DSM-III-R diagnoses of anxiety and depression, SCL-90R scores (all repeatedly ascertained) and with Freiburg Personality Inventory results at age 30 years. Adult psychopathology, personality deviations, and negative affectivity were not connected with early or later separation, but with a report of family strain and childhood disturbances. As variables associated with later psychiatric symptoms and disorder, interpersonal and subjective aspects of childhood out-weigh the fact of separation from parents.


Attenuation of Synaptic Potentials in Dendritic Spines.
Dendritic spines receive the majority of excitatory inputs in many mammalian neurons, but their biophysical properties and exact role in dendritic integration are still unclear. Here, we study spine electrical properties in cultured hippocampal neurons using an improved genetically encoded voltage indicator (ArcLight) and two-photon glutamate uncaging. We find that back-propagating action potentials (bAPs) fully invade dendritic spines. However, uncaging excitatory post-synaptic potentials (uEPSPs) generated by glutamate photorelease, ranging from 4 to 27 mV in amplitude, are attenuated by up to 4-fold as they propagate to the parent dendrites. Finally, the simultaneous occurrence of bAPs and uEPSPs results in sublinear summation of membrane potential. Our results demonstrate that spines can behave as electric compartments, reducing the synaptic inputs injected into the cell, while receiving bAPs are unmodified. The attenuation of EPSPs by spines could have important repercussions for synaptic plasticity and dendritic integration.


Comparison of two methods of encapsulation of an oligonucleotide into poly(D,L-lactic acid) particles.
The aim of this study was to compare two methods to encapsulate a 25-mer-phosphorothioate oligonucleotide (ODN) into poly(D,L-lactic acid) (PLA) particles. Antisense oligonucleotides belong to a new therapeutic class especially attractive for the treatment of cancers and viral diseases. The development of these new drugs suffers, however, from poor stability in biological media and very low cellular uptake. Polymeric particulate systems display interesting features for ODN delivery. ODN are highly hydrophilic and most encapsulation methods are inappropriate for such molecules. Using poly(D,L-lactide) polymer, two methods of encapsulation were compared. First, a double emulsion technique was used to prepare nano- and microparticles. Secondly, the ODN was combined with a quaternary ammonium, the cethyltrimethyl-ammonium bromide (CTAB), to enhance the hydrophobicity of the molecule before entrapment by the emulsification-diffusion method. Both methods led to the formation of individualized and spherical particles loaded with a significant amount of ODN. Similar entrapment efficiencies were obtained for the nanoparticles prepared by both methods (approx. 27% of the theoretical loading) whereas 45% of entrapment efficiency was observed for the microparticles. Seventy five percent of the ODN were released in 60 min with the particles prepared by the emulsification-diffusion method, whereas only 7% were released in 60 h when using the double emulsion method. A viability test on U-937 cells showed better survival rates with the particles prepared by the double emulsion technique. The results suggest that the location of the ODN in the polymeric matrix is affected by the encapsulation method. Particles containing CTAB appeared more toxic than the ones obtained by the double emulsion technique, however, these particles can still be used for antisense activity since high oligonucleotide loading can be achieved.


Financing health improvements in India.
India faces major challenges in sustaining the health gains achieved in the better-performing states and ensuring that the lagging states catch up with the rest of the country. In this paper we examine the current status of health financing in India, as well as alternatives for realizing maximal health gains for the incremental spending. A principal conclusion is that public expenditures of an additional US$6-US$7 per person per year (about 1 percent of gross domestic product) would, if focused on about sixteen key interventions, provide universal access to those interventions and have a favorable affect on population health.


Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases.
Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients. In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests. Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens. We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.


Continuously tunable laser emission from the deep ultraviolet to the near infrared generated by a single optical system.
A two-color laser beam separated by 587 cm(-1)is focused into a Raman cell pressurized with hydrogen. More than fifty rotational and vibrational lines are generated by a four-wave mixing-assisted stimulated Raman effect. By synchronously changing the laser frequencies, the overall tuning range is extended from the deep ultraviolet (247 nm) to the near infrared (771 nm) without any frequency gaps.


Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning.
Bone morphogenetic proteins (BMPs) participate in the development of nearly all organs and tissues. BMP signaling is mediated by specific Smad proteins, Smad1 and/or Smad5, which undergo serine phosphorylation in response to BMP-receptor activation and are then translocated to the nucleus where they modulate transcription of target genes. We have identified a distantly related member of the Xenopus Smad family, Smad8, which lacks the C-terminal SSXS phosphorylation motif present in other Smads, and which appears to function in the BMP signaling pathway. During embryonic development, the spatial pattern of expression of Smad8 mirrors that of BMP-4. We show that an intact BMP signaling pathway is required for its expression. Overexpression of Smad8 in Xenopus embryos phenocopies the effect of blocking BMP-4 signaling, leading to induction of a secondary axis on the ventral side of intact embryos and to direct neural induction in ectodermal explants. Furthermore, Smad8 can block BMP-4-mediated induction of ventral mesoderm-specific gene expression in ectodermal explants. Overexpression of Smad8 within dorsal cells, however, causes patterning defects that are distinct from those reported in BMP-4-deficient embryos, suggesting that Smad8 may interact with additional signaling pathways. Indeed, overexpression of Smad8 blocks expression of Xbra in whole animals, and partially blocks activin signaling in animal caps. In addition, Smad8 inhibits involution of mesodermal cells during gastrulation, a phenotype that is not observed following blockade of activin or BMPs in Xenopus. Together, these results are consistent with the hypothesis that Smad8 participates in a negative feedback loop in which BMP signaling induces the expression of Smad8, which then functions to negatively modulate the amplitude or duration of signaling downstream of BMPs and, possibly, downstream of other transforming growth factor-beta (TGF-beta) family ligands.


A standardized enzyme-linked immunosorbent assay for infectious bronchitis virus: comparison with hemagglutination-inhibition and virus-neutralization assays for measuring protective antibody levels in chickens.
An enzyme-linked immunosorbent assay (ELISA) was developed to measure antibodies to infectious bronchitis virus (IBV) in chickens. The results are reported in IBV standard ELISA values calculated by comparing antibody levels in test sera with antibody levels in a series of standard reference sera. The IBV standard ELISA values were good indicators of responses to vaccination and the immune status of experimentally challenged birds. Although the assay was not serotype-specific, the sensitivity makes it ideally suited for determining the immune status of poultry flocks. The assay results compared favorably with other laboratory results, including virus-neutralization titers, hemagglutination-inhibition levels in sera, virus isolation from vaccinated/challenged birds, and the tracheal ring test results.


How the COVID-19 pandemic changed the Plastic Surgery activity in a regional referral center in Northern Italy.
The Covid 19 epidemic has modified the way that plastic surgeons can treat their patients. At our hospital all elective surgery was canceled and only the more severe cases were admitted. The outpatient department activity has been reduced also. We present the number and diagnoses of patients, treated as in- and out-patients, during seven weeks from the onset of the epidemic, comparing our activity from the lockdown of elective surgery with the numbers and diagnoses observed during the same weeks of last year. Finally we underline the importance of using telemedicine and web-based tools to transmit images of lesions that need the surgeon's evaluation, and can be used by the patient to keep in touch with a doctor during the distressing time of delay of the expected procedure.


Computational modeling and molecular physiology experiments reveal new insights into shoot branching in pea.
Bud outgrowth is regulated by the interplay of multiple hormones, including auxin, cytokinin, strigolactones, and an unidentified long-distance feedback signal that moves from shoot to root. The model of bud outgrowth regulation in pea (Pisum sativum) includes these signals and a network of five RAMOSUS (RMS) genes that operate in a shoot-root-shoot loop to regulate the synthesis of, and response to, strigolactones. The number of components in this network renders the integration of new and existing hypotheses both complex and cumbersome. A hypothesis-driven computational model was therefore developed to help understand regulation of shoot branching. The model evolved in parallel with stepwise laboratory research, helping to define and test key hypotheses. The computational model was used to verify new mechanisms involved in the regulation of shoot branching by confirming that the new hypotheses captured all relevant biological data sets. Based on cytokinin and RMS1 expression analyses, this model is extended to include subtle but important differences in the function of RMS3 and RMS4 genes in the shoot and rootstock. Additionally, this research indicates that a branch-derived signal upregulates RMS1 expression independent of the other feedback signal. Furthermore, we propose xylem-sap cytokinin promotes sustained bud outgrowth, rather than acting at the earlier stage of bud release.


A new approach to quantifying morphological variation in bluegill Lepomis macrochirus.
Bluegill Lepomis macrochirus showed intraspecific morphological and behavioural differences dependent on the environment. Pelagic L. macrochirus had more fusiform bodies, a higher pectoral fin aspect ratio, a larger spiny dorsal fin area and pectoral fins located farther from the centre of mass than littoral L. macrochirus (P < 0·05). The shape of the body and pectoral fins, in particular, were suggestive of adaptation for sustained high-speed and economical labriform swimming. Littoral L. macrochirus had a deeper and wider body, deeper caudal fins and wider mouths than pelagic L. macrochirus (P < 0·05). Additionally, the soft dorsal, pelvic, anal and caudal fins of littoral L. macrochirus were positioned farther from the centre of mass (P < 0·05). The size and placement of these fins suggested that they will be effective in creating turning moments to facilitate manoeuvring in the macrophyte-dense littoral habitat.


Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia.
Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ.


Association between low serum ferritin and restless legs syndrome in patients with attention deficit hyperactivity disorder.
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive inattention and/or hyperactivity-impulsivity. It has been suggested that ADHD symptoms are associated with restless legs syndrome (RLS), which is a neurological condition that is defined by an irresistible urge to move the legs. Increasing evidence suggests iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD and with RLS. To further define the relationship between iron deficiency and RLS in children and adolescents with ADHD, we evaluated 87 ADHD subjects: 79 boys and 8 girls with age 9.3 +/- 2.5 years (6-16 years). Various psychopathologies and the severity of the ADHD symptoms and serum ferritin levels were assessed. Diagnosis of RLS was made according to the International RLS Group criteria. The patients were evaluated for the iron deficiency (ferritin < 12 ng/ml). RLS was found in 29 (33.3%) of the 87 ADHD subjects. Parent- and teacher-rated behavioral and emotional problems and the severity of ADHD symptoms were not significantly different between ADHD subjects with RLS and those without RLS (n = 58). The rate of iron deficiency was significantly higher in ADHD subjects with RLS (n = 6, 20.7%) when compared with ADHD subjects without RLS (n = 1, 1.7%, p = 0.005). Our results showed that depleted iron stores might increase the risk of having RLS in ADHD subjects. Iron deficiency, which is associated with both ADHD and RLS, seems to be an important modifying factor in the relationship between these two conditions.


The risk of worsening CHF is positively related to unitary increase in mitral regurgitation size: a case-cohort study derived from a II NYHA class CHF patient population.
The passage from II to III New York Heart Association (NYHA) class is indicative of cardiopulmonary impairment and unfavourable prognosis. Among chronic heart failure(CHF) II NYHA class patients, the topic has been debated what criteria have be assumed for identifying the patients prone to accelerated progression towards III NYHA class. A case cohort study, including a number of CHF II NYHA class patients, was carried out, to evaluate the role as predictor of CHF worsening of some ultrasonographic parameters, listed as follows: left ventricular ejection fraction, as continuous and as a dichotomous variable, i.e. subdivided as follows: 1) LVEF larger than 40% and 2) LVEF ranged from 30% to 40%; mitral regurgitation (MR), as continuous and as a dichotomic variable (i.e. moderate-to-severe MR, defined by transmitralic jet planimetric area estimated as larger than 20% of left atrium area), restrictive LV filling pattern and pulmonary systolic arterial pressure >40 mmHg. The pts were subdivided in 3 categories, as follows:1) diastolic CHF, i.e. heart failure with normal or only mildly impaired left ventricular ejection fraction - 20 patients; 2) systolic CHF, i.e. heart failure with reduced left ventricular ejection fraction - 19 patients; and 3) CHF due to "organic" mitral insufficiency-19 patients. All patients were treated with pharmacologic therapy, according to their respective clinical features and typology of basal heart disease. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the composite endpoint death and hospitalization due to worsening CHF were investigated, concerning each of the above-mentioned criteria. Moreover, the odds ratios (OR) were calculated, by not conditional logistic regression analysis, to achieve information about risk of death and/or worsening CHF, as well as the respective profiles of risk, assessed by relative risk (RR). From 173 followed-up patients, 58 patients,70+/-12 aged, whose 15 cases (transition to III NYHA class) and 43 controls, were included in retrospective analysis. Notewhorty, moderate-to-severe MR only seemed to play a role as reliable predictor of worsening CHF(sensitivity: 93.3%; specificity: 69.7%; PPV: 51.8%; NPV: 96.7%; RR:15.93; OR: 32.3), as its sensitivity and PPV, particularly, were shown to exceed far and away the values of sensitivity and PPV associated to each of other echographic and/or clinical variables. Nevertheless, at multivariate analysis,MR expressed as continuous variable only, but not as "categorical" variable-was demonstrated to independently predict the transition from II to III NYHA class, over two years clinical follow up. The present data seem to support the view that the larger regurgitant jet of mitral insufficiency, the higher the risk of worsening CHF during a two years follow up. Likewise, it is plausible the moderate-severe MR represents a predictor of increased risk of transition to III NYHA class among the CHF II NYHA class patients. In addition, this study seems to indicate that a surgical therapy (prosthetic replacement or mitral valvuloplasty)should always be planned in the case of II NYHA class CHF patient who has been recognized affected by moderate-to-severe MR, since the chances of successful pharmacological prevention of clinical impairment in this setting turned out to be very slight.


Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine.
It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.


Personality correlates of anxiety about public speaking.
McCroskey (1982) has hypothesized that there are various forms of apprehension about communication some of which are situation specific and some of which are best thought of as traits. Other research has established a relationship between personality variables and a trait conception of apprehension about communication. If McCroskey's distinction between trait and situation-based state is appropriate, personality variables ordinarily associated with trait apprehension about communication should not correlate as highly with forms defined as more situation specific, such as anxiety about public speaking. Multiple regressions were performed using trait measures of apprehension about communication (the Personal Report of Communication Apprehension) and situation-based anxiety (the public speaking factor of the Personal Report of Communication Apprehension) as dependent variables. As hypothesized, contributions of personality were less for trait than situation-specific apprehension about communication. The inclusion of self-monitoring as a moderator variable added additional information about the contributions of personality to situation-specific apprehension about communication, with personality being more predictive of apprehension about public speaking for low self-monitors.


Three novel mutations in SQSTM1 identified in familial Paget's disease of bone.
Mutations in Sequestosome 1 (SQSTM1) have been shown to segregate with familial Paget's disease of bone (PDB). We examined the coding sequence of SQSTM1 in five PDB pedigrees and found three novel mutations clustered around the C-terminal ubiquitin associated domain. Disruptions of the C-terminal domain of SQSTM1 seem to be a leading cause of familial PDB. The characteristic features of Paget's disease of bone (PDB) are caused by focal areas of excessive and uncoordinated bone remodeling. A total of seven genetic loci (PDB1-PDB7) have been reported to be associated with the disease. The gene for Sequestosome 1 (p62; SQSTM1) has been identified as the causative gene for PDB3 in numerous French-Canadian families and families predominantly of British descent. To date, a total of three mutations, all affecting the ubiquitin-associated domain of SQSTM1, have been identified: a single 1215 C to T (P392L) transversion in exon 8, a T insertion in exon 8 (E396X), and a G to A mutation at the splice junction of exon 7 (IVS7 + 1). DNA was isolated from blood collected from the members of five U.S. PDB pedigrees. Mutation analysis of the coding sequence of the SQSTM1 gene was performed on the proband and other key individuals in the pedigrees. Four of the five families had SQSTM1 mutations. Three of these mutations were novel: a single base deletion in exon 8 at position 1210 (1210delT) resulting in a premature stop codon at amino acid 394, a single C deletion in exon 8 at position 1215 (1215delC) also resulting in a premature stop codon at amino acid 394, and a single 1200 C to T (P387L) transversion in exon 7. Noteworthy is the fact that these three SQSTM1 mutations, in addition to the three previously described mutations, are clustered near the C-terminal of the protein. These mutations may be acting in a dominant-negative fashion to disrupt the ubiquitin-binding function, which could result in abnormal activation of the NF-kappaB pathway and the subsequent activation of the osteoclasts. These findings imply that SQSTM1 mutations may play a role in the majority of familial PDB in the United States.


Ocean Stratification Impacts on Dissolved Polycyclic Aromatic Hydrocarbons (PAHs): From Global Observation to Deep Learning.
Ocean stratification plays a crucial role in many biogeochemical processes of dissolved matter, but our understanding of its impact on widespread organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), remains limited. By analyzing dissolved PAHs collected from global oceans and marginal seas, we found different patterns in vertical distributions of PAHs in relation to ocean primary productivity and stratification index. Notably, a significant positive logarithmic relationship (R2 = 0.50, p < 0.05) was observed between the stratification index and the PAH stock. To further investigate the impact of ocean stratification on PAHs, we developed a deep learning neural network model. This model incorporated input variables determining the state of the seawater or the stock of PAHs. The modeled PAH stocks displayed substantial agreement with the observed values (R2 ≥ 0.92), suggesting that intensified stratification could prompt the accumulation of PAHs in the water column. Given the amplified effect of global warming, it is imperative to give more attention to increased ocean stratification and its impact on the environmental fate of organic pollutants.


A novel method for computerized measurement of episcleral venous pressure in humans.
Episcleral venous pressure (EVP) is an important determinant of intraocular pressure (IOP) and can be estimated by the pressure required to compress an episcleral vein. However, the lack of objective measurement endpoints makes EVP measurements in humans uncertain. To address this issue, we developed a new method to measure EVP objectively and reproducibly, and demonstrated its utility on a group of normal subjects. Our system for pressure chamber based venomanometry included a computer-controlled motor drive to increase pressure automatically, a transducer to record pressure, and a high-definition video camera to record vein collapse. Pressure measurements were synchronized with the video stream to determine the pressure required to collapse the vein to a specific pre-determined degree. This system was used to measure EVP in 10 eyes from 5 young healthy volunteers. Episcleral veins were selected in each of 4 quadrants. EVP was calculated to be the pressure in the chamber that compressed the vein by 0% (by back-projection), 10% or 50% as determined by using image analysis of the video stream. For this group of subjects, mean EVP was 6.3 ± 2.8 mmHg (mean ± SD, n = 40 measurements), 7.0 ± 2.6 mmHg, and 9.6 ± 2.6 mmHg using the 0%, 10% and 50% reduction endpoints, respectively. Pressures and standard deviations determined from these endpoints were significantly different from each other (p < 0.001). Coefficients of variation between right and left eyes were 12.7%, 10.2%, and 6.8% using the 0%, 10% and 50% endpoints, respectively. Based on previous research and theoretical considerations, the 0% endpoint is assumed to provide the most accurate estimate of baseline EVP, and can only be estimated by analyzing the brightness profiles of the vessels in the video stream. Objective measurement of EVP is important for understanding normal aqueous humor dynamics and its changes in disease states and with therapies. EVP has typically been assumed to be constant because of the lack of a convenient means of its measurement. This new method provides a precise means to assess EVP based on specific endpoints of vessel collapse, and enables, for the first time, objective and non-invasive measurements of EVP changes.


Active Surveillance Cultures and Decolonization to Reduce Staphylococcus aureus Infections in the Neonatal Intensive Care Unit.
Staphylococcus aureus is a common cause of healthcare-associated infections in neonates. To examine the impact of methicillin-susceptible S. aureus (MSSA) decolonization on the incidence of MSSA infection and to measure the prevalence of mupirocin resistance. We retrospectively identified neonates admitted to a tertiary care neonatal intensive care unit (NICU) from April 1, 2011, through September 30, 2014. We compared rates of MSSA-positive cultures and infections before and after implementation of an active surveillance culture and decolonization intervention for MSSA-colonized neonates. We used 2 measurements to identify the primary outcome, NICU-attributable MSSA: (1) any culture sent during routine clinical care that grew MSSA and (2) any culture that grew MSSA and met criteria of the National Healthcare Safety Network's healthcare-associated infection surveillance definitions. S. aureus isolates were tested for mupirocin susceptibility. We estimated incidence rate ratios using interrupted time-series models. Before and after the intervention, 1,523 neonates (29,220 patient-days) and 1,195 neonates (22,045 patient-days) were admitted to the NICU, respectively. There was an immediate reduction in the mean quarterly incidence rate of NICU-attributable MSSA-positive clinical cultures of 64% (incidence rate ratio, 0.36 [95% CI, 0.19-0.70]) after implementation of the intervention, and MSSA-positive culture rates continued to decrease by 21% per quarter (incidence rate ratio, 0.79 [95% CI, 0.74-0.84]). MSSA infections also decreased by 73% immediately following the intervention implementation (incidence rate ratio, 0.27 [95% CI, 0.10-0.79]). No mupirocin resistance was detected. Active surveillance cultures and decolonization may be effective in decreasing S. aureus infections in NICUs.


Explainable AI-based clinical decision support system for hearing disorders.
In clinical system design, human-computer interaction and explainability are important topics of research. Clinical systems need to provide users with not only results but also an account of their behaviors. In this research, we propose a knowledge-based clinical decision support system (CDSS) for the diagnosis and therapy of hearing disorders, such as tinnitus, hyperacusis, and misophonia. Our prototype eTRT system offers an explainable output that we expect to increase its trustworthiness and acceptance in the clinical setting. Within this paper, we: (1) present the problem area of tinnitus and its treatment; (2) describe our data-driven approach based on machine learning, such as association- and action rule discovery; (3) present the evaluation results from the inference on the extracted rule-based knowledge and chosen test cases of patients; (4) discuss advantages of explainable output incorporated into a graphical user interface; (5) conclude with the results achieved and directions for future work.


Long-term exposure to air pollution and type 2 diabetes mellitus in a multiethnic cohort.
Although air pollution has been suggested as a possible risk factor for type 2 diabetes mellitus (DM), results from existing epidemiologic studies have been inconsistent. We investigated the associations of prevalence and incidence of DM with long-term exposure to air pollution as estimated using annual average concentrations of particulate matter with an aerodynamic diameter of 2.5 μm or less (PM₂.₅) and nitrogen oxides at baseline (2000) in the Multi-Ethnic Study of Atherosclerosis. All participants were aged 45-84 years at baseline and were recruited from 6 US sites. There were 5,839 participants included in the study of prevalent DM and 5,135 participants without DM at baseline in whom we studied incident DM. After adjustment for potential confounders, we found significant associations of prevalent DM with PM₂.₅ (odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.00, 1.17) and nitrogen oxides (OR = 1.18, 95% CI: 1.01, 1.38) per each interquartile-range increase (2.43 µg/m(3) and 47.1 ppb, respectively). Larger but nonsignificant associations were observed after further adjustment for study site (for PM₂.₅, OR = 1.16, 95% CI: 0.94, 1.42; for nitrogen oxides, OR = 1.29, 95% CI: 0.94, 1.76). No air pollution measures were significantly associated with incident DM over the course of the 9-year follow-up period. Results were partly consistent with a link between long-term exposure to air pollution and the risk of type 2 DM. Additional studies with a longer follow-up time and a greater range of air pollution exposures, including high levels, are warranted to evaluate the hypothesized association.


Extreme lateral interbody fusion approach for isolated thoracic and thoracolumbar spine diseases: initial clinical experience and early outcomes.
Retrospective review of prospective collected data on 22 patients. To describe our initial clinical experience and outcomes with the extreme lateral interbody fusion (XLIF) approach for spinal diseases requiring access to the thoracic cavity. Minimally invasive anterior approaches to the thoracic spine have traditionally consisted of thoracoscopic and mini-open thoracotomy techniques. We present our initial experience with employing the XLIF technique to treat thoracic spine diseases. Clinical, radiographic, operative, postoperative, and functional outcomes were analyzed. A total of 22 patients (15 females, 7 males, average age 64.6 y) with isolated thoracic and thoracolumbar spine diseases were treated between 2005 and 2009. The indications for surgery included degenerative scoliosis (11), pathological fractures from tumors (2), adjacent level disease from prior fusions (5), thoracic disc herniations (3), and discitis/osteomyelitis (1). A total of 47 levels were treated. In the subset of patients treated for degenerative scoliosis, the mean preoperative and postoperative coronal Cobb angles were 22 and 14, respectively. The mean preoperative and postoperative sagittal angles were 39 and 44, respectively. The average estimated blood loss and length of stay were 227.5 mL and 4.8 d, respectively. Three complications consisting of wound infection, subsidence, and adjacent level disease requiring additional procedures were encountered. There were no neural, vascular, visceral injuries, or death. At a mean follow-up of 16.4 months (range, 3-50), we observed a 95.5% substantial clinical benefit. All patients who had reached a minimum of 6 months (95.5%) demonstrated radiographic evidence of fusion. The XLIF technique can be expanded to treat diseases in the thoracic spine. Although the magnitude of deformity correction achieved is less than that of the traditional open approaches, the lesser invasiveness of this technique may be tolerable for the elderly and in patients with significant medical comorbidities.


Economic evaluations of artificial intelligence-based healthcare interventions: a systematic literature review of best practices in their conduct and reporting.
Objectives: Health economic evaluations (HEEs) help healthcare decision makers understand the value of new technologies. Artificial intelligence (AI) is increasingly being used in healthcare interventions. We sought to review the conduct and reporting of published HEEs for AI-based health interventions. Methods: We conducted a systematic literature review with a 15-month search window (April 2021 to June 2022) on 17th June 2022 to identify HEEs of AI health interventions and update a previous review. Records were identified from 3 databases (Medline, Embase, and Cochrane Central). Two reviewers screened papers against predefined study selection criteria. Data were extracted from included studies using prespecified data extraction tables. Included studies were quality assessed using the National Institute for Health and Care Excellence (NICE) checklist. Results were synthesized narratively. Results: A total of 21 studies were included. The most common type of AI intervention was automated image analysis (9/21, 43%) mainly used for screening or diagnosis in general medicine and oncology. Nearly all were cost-utility (10/21, 48%) or cost-effectiveness analyses (8/21, 38%) that took a healthcare system or payer perspective. Decision-analytic models were used in 16/21 (76%) studies, mostly Markov models and decision trees. Three (3/16, 19%) used a short-term decision tree followed by a longer-term Markov component. Thirteen studies (13/21, 62%) reported the AI intervention to be cost effective or dominant. Limitations tended to result from the input data, authorship conflicts of interest, and a lack of transparent reporting, especially regarding the AI nature of the intervention. Conclusion: Published HEEs of AI-based health interventions are rapidly increasing in number. Despite the potentially innovative nature of AI, most have used traditional methods like Markov models or decision trees. Most attempted to assess the impact on quality of life to present the cost per QALY gained. However, studies have not been comprehensively reported. Specific reporting standards for the economic evaluation of AI interventions would help improve transparency and promote their usefulness for decision making. This is fundamental for reimbursement decisions, which in turn will generate the necessary data to develop flexible models better suited to capturing the potentially dynamic nature of AI interventions.


Individual-level and socio-structural characteristics of violence: an Emergency Department study.
In this article, the authors present a data collection system to provide information about assault-related injuries within Newark, New Jersey. In 2001, Emergency Department (ED) staff at the six hospitals providing emergency medical care within the city collected data on all assault-related ED visits. Individual-level (n = 1,204) and neighborhood-level (n = 262) analyses were conducted; the latter used data from the 2000 U.S. Census. A hotspots map was also generated. At the individual level, one in three ED patients was assaulted by an intimate partner or other family member. In addition, African American males were disproportionately likely to be treated for assault-related injuries. At the socio-structural level, as hypothesized based on Social Disorganization Theory, hierarchical regression analyses reveal that poorer neighborhoods with more vacant housing units have significantly higher rates of assault-related injuries.


Parapleurogonius brevicecum gen. et sp. n. (Trematoda: Pronocephalidae) from a freshwater turtle in peninsular Malaysia.
Parapleurogonius brevicecum gen. et sp. n. is described from the freshwater turtle, Kachuga trivittata, in Selangor, Malaysia. Parapleurogonius is most closely related to Pleurogonius Looss, 1901, but from which it can be distinguished by the termination of the ceca at or just overlapping the anterior border of the testes and the pretesticular position of the excretory pore. Additionally, Parapleurogonius is described from a freshwater turtle, whereas Pleurogonius is only known from marine hosts.


Neuronal activity patterns in the developing barrel cortex.
The developing barrel cortex reveals a rich repertoire of neuronal activity patterns, which have been also found in other sensory neocortical areas and in other species including the somatosensory cortex of preterm human infants. The earliest stage is characterized by asynchronous, sparse single-cell firing at low frequencies. During the second stage neurons show correlated firing, which is initially mediated by electrical synapses and subsequently transforms into network bursts depending on chemical synapses. Activity patterns during this second stage are synchronous plateau assemblies, delta waves, spindle bursts and early gamma oscillations (EGOs). In newborn rodents spindle bursts and EGOs occur spontaneously or can be elicited by sensory stimulation and synchronize the activity in a barrel-related columnar network with topographic organization at the day of birth. Interfering with this early activity causes a disturbance in the development of the cortical architecture, indicating that spindle bursts and EGOs influence the formation of cortical columns. Early neuronal activity also controls the rate of programed cell death in the developing barrel cortex, suggesting that spindle bursts and EGOs are physiological activity patterns particularly suited to suppress apoptosis. It remains to be studied in more detail how these different neocortical activity patterns control early developmental processes such as formation of synapses, microcircuits, topographic maps and large-scale networks.


Prior authorization delays biologic initiation and is associated with a risk of asthma exacerbations.
Background: Biologics are effective treatments for patients with severe allergic disease. Impacts of delays in the prior authorization process on clinical outcomes has not been studied. Objective: The objective was to quantify the times for approval and filling of biologics, and whether patients were at risk of exacerbations during this time frame. Methods: The times for insurance approval and pharmacy filling of biologics (omalizumab, benralizumab, mepolizumab, dupilumab) in 80 subjects with severe asthma (n = 60) or urticaria (n = 20) from our clinic were reviewed. We compared the impact of clinical features, insurance, specialty pharmacy on fill times, and quantified exacerbations and prednisone use while awaiting biologic initiation. Results: The mean ± standard deviation (SD) time (days) from submission of a prescription to the first dose available for injection was 44.0 ± 23.2 days. This was composed of the mean ± SD time for insurance approval (21.5 ± 19.6 days) and the mean ± SD time for a specialty pharmacy to fill the medication (22.8 ± 14.1 days). There was no significant difference between the times for diagnosis (asthma versus urticaria), specific biologic, or insurance. The "buy and bill" system was faster than filling via a specialty pharmacy (mean ± SD, 7.3 ± 8.5 days versus 23.3 ± 21.3 days, respectively, p < 0.001). Clinical features of patients with fast versus slow approval times was not significantly different. The subjects with asthma were at high risk of exacerbations and need for prednisone while awaiting initiation of the biologics; 28 of 59 patients (47%) required prednisone, with an mean cumulative dose of 483.2 ± 273.7 mg per person. Conclusion: The prior authorization process for biologics was slow, and the subjects were at high risk of exacerbations during this time. The system needs to be improved to expedite approval and initiation of these medications.


Calcium regulates human CYP11B2 transcription.
The CYP11B2 gene encodes aldosterone synthase, a cytochrome P450 (P450aldo) expressed in high levels in the adrenal zona glomerulosa. While the primary physiologic regulators of aldosterone production are circulating angiotensin II (Ang II) and potassium (K+) the action of these agents on CYP11B2 gene transcription have not been examined. Because these factors increase intracellular calcium we have hypothesized that calcium signaling pathways are one mechanism controlling CYP11B2 transcription. Previously we demonstrated that increases in intracellular calcium increase P450aldo mRNA. Herein, we analyzed the role of calcium in the expression of the human CYP11B2 gene using transient transfection of a luciferase reporter construct containing 2017 bp of human CYP11B2 5'flanking DNA in mouse Y-1 and human H295R adrenocortical cell lines. When transfected into Y-1 cells, reporter gene expression was increased following treatment with ACTH or forskolin, but not with Ang II, the L-type calcium channel agonist BAYK8644, or ionomycin. In H295R cells, however, reporter gene expression was increased following treatment with Ang II, K+, BAYK8644 ionomycin or dibutyryl cAMP (Bu2cAMP). Activation of protein kinase C with TPA did not alter reporter gene expression in either cell line. These data demonstrate that both calcium and cAMP signaling pathways regulate human CYP11B2 gene expression. In addition, the H295R adrenal cell line appears to be an appropriate model to study regulation of CYP11B2 by calcium.


Mapping factors that may influence attrition and retention of midwives: a scoping review protocol.
An appropriately staffed midwifery workforce is essential for the provision of safe and high-quality maternity care. However, there is a global and national shortage of midwives. Understaffed maternity services are frequently identified as contributing to unsafe care provision and adverse outcomes for mothers and babies. While there is a need to recruit midwives through pre-registration midwifery programmes, this has significant resource implications, and is counteracted to a large extent by the high number of midwives leaving the workforce. It is increasingly recognised that there is a critical need to attend to retention in midwifery in order to develop and maintain safe staffing levels. The objective of this review is to collate and map factors that have been found to influence attrition and retention in midwifery. Joanna Briggs Institute guidance for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews will be used to guide the review process and reporting of the review. CINAHL, MEDLINE, PsycINFO and Scopus databases will be searched for relevant literature from date of inception to 21 July 2023. Research from high-income countries that explores factors that influence leaving intentions for midwives will be included. Literature from low-income and middle-income countries, and studies where nursing and midwifery data cannot be disaggregated will be excluded. Two reviewers will screen 20% of retrieved citations in duplicate, the first author will screen the remaining results. Data will be extracted using a preformed data extraction tool by the first author. Findings will be presented in narrative, tabular and graphical formats. The review will collate data from existing research, therefore ethics approval is not required. Findings will be published in journals, presented at conferences and will be translated into infographics and other formats for online dissemination.


Single-Step Transepithelial Photorefractive Keratectomy in Low to Moderate Myopia: A One-Year Follow-Up Study.
To evaluate predictability, safety, efficacy, and visual outcome of StreamLight. ™ (SL.), the newly released single-step transepithelial photorefractive keratectomy platform by Alcon WaveLight™ (WL). In this prospective cohort study, photorefractive keratectomy (PRK) was conducted on 500 eyes of 250 patients seeking myopic refractive vision correction. The new single-step transepithelial PRK method was applied, using the SL. platform installed in the WL. Ex 500 excimer laser machine. Patients were followed up to monitor intensity and duration of postoperative pain, as well as speed of epithelial healing in the early post-operative period and visual acuity, postoperative refraction and development of postoperative haze for one year post-operatively. Average pain duration was 1.5 days, and the mean pain intensity score on a scale of 0-10 was 3.74 + 1.51. Mean postoperative spherical equivalence was 0.01 ± 0.38 D, and the final postoperative uncorrected distance visual acuity (UCDVA) was 20/20 in 98% of eyes included in this study. None of the eyes lost more than one Snellen chart line or developed visually significant postoperative haze during the follow-up period. The new SL. platform for transepithelial PRK is a safe, accurate platform, offering an easier early post-operative recovery, with no compromise in final visual outcome.


Development of a facile electrochemical sensor based on GCE modified with one-step prepared PNMA-CeO2-fMWCNTs composite for simultaneous detection of UA and 5-FU.
In this study, a poly(N-methyl aniline)-cerium oxide-functionalized MWCNTs (PNMA-CeO2-fMWCNTs) composite was synthesized in a one-step preparation technique. As a highly efficient modifier, the composite was used to modify the glassy carbon electrode surface for simultaneous detection of uric acid (UA) and 5-fluorouracil (5-FU). Morphological characterization of the GCE/PNMA-CeO2-fMWCNTs was studied using scanning electron microscopy. Structural characterization of the composite was performed using X-ray diffraction and Fourier-transformed infrared spectroscopy. Electron transfer properties of the prepared electrodes were carried out with electrochemical impedance spectroscopy and cyclic voltammetry. The linear working range for UA and 5-FU was found to be 0.25-50 μM and 0.5-750 μM, respectively. The limit of detection values for UA and 5-FU were 0.04 μM and 0.19 μM, respectively. The effects of various interfering substances on the electrochemical response of UA and 5-FU were investigated. The GCE/PNMA-CeO2-fMWCNTs sensor has excellent stability, reproducibility, anti-interference ability, and reproducibility. To demonstrate the practical application of the sensing platform, fetal bovine serum was selected and tested in the spiked samples, and satisfactory results were obtained. The prepared composite proved to be a promising platform for simple, rapid, and simultaneous analysis of UA and 5-FU.


Ethnic group variations in alcohol-related hospital admissions in England: does place matter?
The health burden of alcohol use is socially and geographically patterned in many countries. Less is known about variations in this burden between ethnic groups and whether this differs across place of residence. National cross-sectional study using hospital admission data in England. Alcohol-related admission rates, where an alcohol-related condition was either the primary diagnosis (considered as the reason for admission) or a comorbidity, were calculated using ethnic group specific rates for English regions. In 2010/11 there were a total of 264,870 alcohol-related admissions in England. Admission rates were higher in the North of England than elsewhere (e.g. for primary diagnosis 161 per 100,000 population in the North vs. 62 per 100,000 in the South). These patterns were not uniform across ethnic groups however. For example, admission rates for alcohol-related comorbidity were four times higher among White Irish in London compared with those in the South of England (306 to 76 per 100,000) and four times higher in Indians living in the Midlands compared with those in the South of England (128 to 29 per 100,000). These patterns were similar for admissions with a comorbid alcohol-related condition. Geographical location may be an important determinant of within and between ethnic group variations in alcohol-related hospital admissions in England. While a number of factors were not examined here, this descriptive analysis suggests that this heterogeneity should be taken into account when planning interventions and services for the prevention and management of alcohol misuse.


Extra-aural spread of acquired cholesteatoma. A report of two unique cases.
The osteolytic effect of inflamed cholesteatoma can result in destruction of the bony confines of the middle ear and mastoid. Although extramastoid extension of cholesteatoma is possible through this mechanism, it is rarely seen by the otolaryngologist. We present two cases of extra-aural spread of cholesteatoma. One case illustrates the necessity of a full neuroradiologic examination of patients with neurologic findings and cholesteatoma prior to exploration of the middle ear and mastoid.


The passage of time in Iraq during the covid-19 pandemic.
The covid-19 global pandemic has influenced the day-to-day lives of people across the world. One consequence of this has been significant distortion to the subjective speed at which people feel like time is passing. To date, temporal distortions during covid-19 have mainly been studied in Europe. The current study therefore sought to explore experiences of the passage of time in Iraq. An online questionnaire was used to explore the passage of time during the day, week and the 11 months since the first period of covid-19 restrictions were imposed in Iraq. The questionnaire also measured affective and demographic factors, and task-load. The results showed that distortions to the passage of time were widespread in Iraq. Participants consistently reported a slowing of the passage of time for the day and the week during the pandemic in comparison to normal (i.e. before the pandemic). Participants also reported that it felt like longer than 11-months since the first lockdown began. The passage of time during the day and week were not predicted by any demographic, affective or task-load measures taken in the study. The perceived length of time since the first lockdown was however predicted by stress and change of life due to covid, with greater stress and greater change of life being associated with greater subjective lengthening of the pandemic. The findings indicate that whilst distortions to the passage of time during covid-19 appear to be a global phenomenon, the factors which predict temporal experience during the pandemic differ between countries and cultures.


The Role of Outpatient Care Accreditation in Enhancing Foreign Patients' Perception of Colombian Medical Tourism: A Quasi-experimental Design.
This study analyzes whether hospitals accredited by the Joint Commission International in outpatient medical care protocols located in Colombia achieve a higher quality perception from foreign patients compared to others treated in a non-accredited one. A t-test with Welch correction, chi-square test, correlation coefficient of Tau Kendall, pre-test, post-test, complementary questionnaire and a 2 focus groups were used in 178 foreign patients. It was observed that patients treated in accredited hospitals had a higher quality perception than the non-accredited group. However, it was found that an unbalanced application of the 3 variables negatively alters quality judgment. Findings contributes to understanding the Colombian medical tourism in depth using non-conventional instruments.


Hubble space telescope observations of comet p/shoemaker-levy 9 (1993e).
The Hubble Space Telescope observed the fragmented comet P/Shoemaker-Levy 9 (1993e) (P indicates that it is a periodic comet) on 1 July 1993. Approximately 20 individual nuclei and their comae were observed in images taken with the Planetary Camera. After subtraction of the comae light, the 11 brightest nuclei have magnitudes between approximately 23.7 and 24.8. Assuming that the geometric albedo is 0.04, these magnitudes imply that the nuclear diameters are in the range approximately 2.5 to 4.3 kilometers. If the density of each nucleus is 1 gram per cubic centimeter, the total energy deposited by the impact of these 11 nuclei into Jupiter's atmosphere next July will be approximately 4 x 10(30) ergs ( approximately 10(8) megatons of TNT). This latter number should be regarded as an upper limit because the nuclear magnitudes probably contain a small residual coma contribution. The Faint Object Spectrograph was used to search for fluorescence from OH, which is usually an excellent indicator of cometary activity. No OH emission was detected, and this can be translated into an upper limit on the water production rate of approximately 2 x 10(27) molecules per second.


Viability and Antioxidant Effects of Traditional Cooling Rice Powder (bedak sejuk) Made from Oryza sativa ssp. Indica and Oryza sativa ssp. japonica on UVB-Induced B164A5 Melanoma Cells.
Traditional cooling rice powder (bedak sejuk) is a fermented rice-based cosmetic that is applied topically on one's skin, as an overnight facial mask. According to user testimonies, bedak sejuk beautifies and whitens skin, whereby these benefits could be utilised as a potential melanoma chemopreventive agent. Hence, this study aimed to determine the effects of bedak sejuk made from Oryza sativa ssp. indica (Indica) and Oryza sativa ssp. japonica (Japonica) on UVB-induced B164A5 melanoma cells, and also identify the antioxidant capacities of both types of bedak sejuk. The optimum dose of Indica and Japonica bedak sejuk to treat the cells was determined via the MTT assay. Then, the antioxidant capacities of both types of bedak sejuk were determined using the FRAP assay. From the MTT assay, it was found that Indica and Japonica bedak sejuk showed no cytotoxic effects towards the cells. Hence, no IC50 can be obtained and two of the higher doses, 50 and 100 g/L were chosen for treatment. In the FRAP assay, Indica bedak sejuk at 50 and 100 g/L showed FRAP values of 0.003 ± 0.001 μg AA (ascorbic acid)/g of bedak sejuk and 0.004 ± 0.0003 μg AA/g of bedak sejuk. Whereas Japonica bedak sejuk at 50 g/L had the same FRAP value as Indica bedak sejuk at 100 g/L. As for Japonica bedak sejuk at 100 g/L, it showed the highest antioxidant capacity with the FRAP value of 0.01 ± 0.0007 μg AA/g of bedak sejuk which was statistically significant (p < 0.05) when compared to other tested concentrations. In conclusion, Japonica bedak sejuk has a higher antioxidant capacity compared to Indica bedak sejuk despite both being not cytotoxic towards the cells. Regardless, further investigations need to be done before bedak sejuk could be developed as potential melanoma chemoprevention agents.


Traditions and myths in hip and knee arthroplasty.
Traditions are passed on from experienced surgeons to younger fellows and become "the right way to do it". Traditions associated with arthroplasty surgery may, however, not be evidence-based and may be potentially deleterious to both patients and society, increasing morbidity and mortality, slowing early functional recovery, and increasing cost. We identified selected traditions and performed a literature search using relevant search criteria (June 2014). We present a narrative review grading the studies according to evidence, and we suggest some lines of future research. We present traditions and evaluate them against the published evidence. Preoperative removal of hair, urine testing for bacteria, use of plastic adhesive drapes intraoperatively, and prewarming of the operation room should be abandoned-as should use of a tourniquet, a space suit, a urinary catheter, and closure of the knee in extension. The safety and efficacy of tranexamic acid is supported by meta-analyses. Postoperatively, there is no evidence to support postponement of showering or postponement of changing of dressings to after 48 h. There is no evidence to recommend routine dental antibiotic prophylaxis, continuous passive motion (CPM), the use of compression stockings, cooling for pain control or reduction of swelling, flexion of at least 90 degrees as a discharge criterion following TKA, or having restrictions after THA. We present evidence supporting the use of NSAIDs, early mobilization, allowing early travel, and a low hemoglobin trigger for transfusion. Revision of traditions and myths surrounding hip and knee arthroplasty towards more contemporary evidence-based principles can be expected to improve early functional recovery, thus reducing morbidity, mortality, and costs.


Strengthening mechanisms of current dental porcelains.
Dental porcelains have a high glass content, which provides the translucency necessary for esthetic restorations. Because glasses are brittle, they fail under tension or bending by the propagation of preexisting flaws (e.g., scratches, porosities). Several approaches that are based on impeding the propagation of flaws have been used to strengthen dental porcelains, including bonding to metals, adding microcrystalline phases, and surface treatments (i.e., polishing, ion exchange, hydration). Through these methods, porcelain systems are used routinely for all-ceramic anterior restorations; however, porcelain-fused-to-metal restorations remain the most reliable for posterior applications.


Phosphatidylserine promotes immunotherapy for airway allergy.
Type 1 regulatory T cells (Tr1 cells) play an important role in the maintenance of the immune homeostasis in the body. The induction of Tr1 cell is to be further investigated. The interaction of phosphatidylserine (PS) with TIM3 has immune regulation functions. The objective of this study is to elucidate the role of PS-TIM3 signals in inducing Tr1 cells. In this study, mice were treated using PS or specific immunotherapy by nasal instillation. A murine model of allergic rhinitis was developed using ovalbumin as a specific antigen. We found that PS-containing nasal instillation induced Tr1 cells in the airway tissues. PS promoted gene activities associated with IL-10 through activation of TIM3 in CD4+ T cells. TIM3 mediated the effects of PS on inducing Tr1 cells, in which the TIM3- PI3K-AKT pathway played a critical role. PS boosted allergen-specific immunotherapy by inducing specific antigen Tr1 cell generation. Concomitant administration of PS and SIT resulted in better therapeutic effects on AR. In conclusion, the data demonstrate that PS can promote the specific immunotherapy for AR through inducing antigen specific Tr1 cells in the airway tissues.


Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults.
A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), has been identified in which proline replaces arginine at codon 259. We determined the influence of TCII genotype on indices of B12 status, including total serum B12, the amount of B12 bound to TCII (holoTCII), methylmalonic acid, and homocysteine, in 128 healthy older adults (ages 40-88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean holoTCII concentration was significantly higher in those subjects homozygous for the proline form of TCII (PP) compared with those homozygous for the arginine form (RR) and heterozygotes (PR) (P <or=.006). In addition, mean methylmalonic acid concentrations were significantly lower in the PP and PR groups compared with the RR group (P <or=.02). The PP genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCII genotype may thus influence susceptibility to B12 deficiency.


Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer: a feasibility trial.
The vitamin D hormone, [1,25(OH) 2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH) 2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D 2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2-7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12-72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.


[Abdominal syndrome in pseudotuberculosis].
The authors observed 41 patients with pseudotuberculosis. In 32 patients, the abdominal syndrome predominated in the clinical course. For this reason, the appendectomy was performed in 30 of them. In 9 patients, the lingering, relapsing course of pseudotuberculosis was noted after the operation.


Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis.
We previously reported that IL-2 deprivation induced acid sphingomyelinase-mediated (ASM-mediated) ceramide elevation and apoptosis in an NK/T lymphoma cell line KHYG-1. However, the molecular mechanism of ASM-ceramide-mediated apoptosis during IL-2 deprivation is poorly understood. Here, we showed that IL-2 deprivation induces caspase-dependent apoptosis characterized by phosphatidylserine externalization, caspase-8, -9, and -3 cleavage, and degradation of X-linked inhibitor of apoptosis protein (XIAP). IL-2 re-supplementation rescued apoptosis via inhibition of XIAP degradation without affecting caspase cleavage. However, IL-2 deprivation induced ceramide elevation via ASM in lysosomes and activated lysosomal cathepsin B (CTSB) but not cathepsin D. A CTSB inhibitor CA-074 Me and knockdown of CTSB inhibited ceramide-mediated XIAP degradation and apoptosis. Inhibition of ceramide accumulation in lysosomes using an ASM inhibitor, desipramine, decreased cytosolic activation of CTSB by inhibiting its transfer into cytosol from the lysosome. Knockdown of ASM also inhibited XIAP degradation and apoptosis. Furthermore, cell permeable N-acetyl sphingosine (C2-ceramide), which increases mainly endogenous d18:1/16:0 and d18:1/24:1 ceramide-like IL-2 deprivation, induced caspase-dependent apoptosis with XIAP degradation through CTSB. These findings suggest that lysosomal ceramide produced by ASM mediates XIAP degradation by activation of cytosolic CTSB and caspase-dependent apoptosis. The ASM-ceramide-CTSB signaling axis is a novel pathway of ceramide-mediated apoptosis in IL-2-deprived NK/T lymphoma cells.


Smoking status, mental disorders and emotional and behavioural problems in young people: child and adolescent component of the National Survey of Mental Health and Wellbeing.
To examine the relationship between smoking behaviour, mental disorders and emotional and behavioural problems in a nationally representative sample of young people. Data were taken from the child and adolescent component of the National Survey of Mental Health and Wellbeing which assessed mental health problems in two main ways: using a fully structured interview (the Diagnostic Interview Schedule for Children) and using the Child Behaviour Checklist and the Youth Self Report, which assess emotional and behavioural problems on a dimensional scale. The relationship between smoking and mental health problems was assessed using logistic regression. Among young people with conduct disorder 72% had smoked in the last 30 days, 46% of young people with depressive disorder, and 38% among young people with attention deficit hyperactivity disorder. This compared with 21% of young people with none of these disorders. Odds ratios (OR) for current smoking were consistently elevated for young people with mental health problems after adjusting for demographic and socio-economic factors across all measures of mental health used. The OR for current smoking in young people with parent-reported externalizing behaviours in the clinical range was 4.5 (95%CI: 3.1-6.8), and for young people with parent-reported internalizing problems in the clinical range the OR was 2.7 (95%CI: 1.8-4.0). Young people with mental health problems started smoking on average at a younger age, were more likely to progress to current smoking, and smoked on average a higher number of cigarettes per day. After adjusting for demographic and socio-economic factors, young people with mental health problems were more likely to start smoking, progress to daily smoking, and smoke more heavily. Mental illness is an important issue to consider in tobacco control in young people.


Economic costs of alcohol consumption in Thailand, 2021.
Alcohol is one of the leading risk factors contributing to avoidable economic loss worldwide. Estimates from the economic cost of alcohol consumption studies play an important role in prioritizing healthcare resource use, supporting policy decisions, and justifying budgets for alcohol policy. This study aimed to estimate the economic burden associated with alcohol consumption in Thailand in 2021. Prevalence-based cost of illness methodology was employed. The following costs were included in the analysis: healthcare costs; cost of law enforcement; cost of property damage due to road traffic accidents; cost of premature mortality; and cost of absenteeism from out-patient hospital visits and hospitalization. Human capital approach was adopted. All costs were presented in Thai baht, 2021. Alcohol consumption incurred a total estimated economic cost of 165,450.5 million baht, equivalent to 1.02% of Gross Domestic Product (GDP) and 2500 baht per capita. Cost of premature mortality was estimated at 157,918.7 million baht and accounted for the largest proportion of the total cost (95.45%). Healthcare cost was found to be the second highest share representing 4370.1 million baht (2.7% of the total cost). The number of premature death attributable to alcohol consumption in 2021 was estimated at 22,804. Alcohol continues to impose a substantial economic burden in Thailand. Enforcement of existing well-formulated alcohol control policies is urgently required to mitigate the economic impact of alcohol consumption in the country.


Lessons about Virtual-Environment Software Systems from 20 years of VE building.
What are desirable and undesirable features of virtual-environment (VE) software architectures? What should be present (and absent) from such systems if they are to be optimally useful? How should they be structured? To help answer these questions we present experience from application designers, toolkit designers, and VE system architects along with examples of useful features from existing systems. Topics are organized under the major headings of: 3D space management, supporting display hardware, interaction, event management, time management, computation, portability, and the observation that less can be better. Lessons learned are presented as discussion of the issues, field experiences, nuggets of knowledge, and case studies.


Relationship between sarcopenic obesity and cardiovascular disease risk as estimated by the Framingham risk score.
This study was conducted to assess the association between sarcopenic obesity and cardiovascular disease (CVD) risk in Korean adults (n=3,320; ≥40 yr) who participated in the 5th Korean National Health and Nutrition Examination Survey in 2010. The appendicular skeletal muscle mass divided by body weight was calculated for each participant; participants with values <1 standard deviation below the mean reference value (i.e., aged 20-39 yr) were considered sarcopenic. Subjects were further classified into 4 groups according to their obesity (i.e., body mass index ≥25 kg/m(2)) and sarcopenic status. Individuals' 10-yr CVD risk was determined using the Framingham risk model. The sarcopenic obese group had more participants (43.8% men, 14.6% women) with a high risk of CVD (≥20%). The sarcopenic obese group was associated with an increased 10-yr CVD risk than the non-sarcopenic, non-obese group (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.53-4.06, P<0.001 in men; OR, 1.87; 95% CI, 1.02-3.41, P=0.041 in women). Sarcopenic non-obese and non-sarcopenic obese subjects were not associated with an increased 10-yr CVD risk. Sarcopenic obesity, but not non-sarcopenic obesity, was closely associated with an increased CVD risk in Korean adults.