One respiratory care department's contribution to the 'bottom line'.
Although many hospital departments that were revenue producers have become cost centers and revenues above expenditures have shrunk, some departments continue to contribute. I analyzed the financial statements of our 240-bed, not-for-profit hospital to determine the Respiratory Care Department's actual contribution to the hospital's 'bottom line' (ie, revenue above expenditures). The Respiratory Care Department's financial statement, the Hospital's profit and loss statement, and the financial statements for all 54 hospital departments were reviewed. Analysis revealed that the Respiratory Care Department's revenue dollar contributed $0.095 to the hospital bottom line for each revenue dollar generated. Analysis also demonstrated that the break-even contribution margin for revenue departments was 76.77%. Departments with contribution margins greater than 76.77% were revenue contributors and those departments with less than 76.77% were cost centers. The Respiratory Care Department was the hospital's largest revenue contributor, generating 42.8% of the hospital's revenue above expenditures. In today's health-care environment, it is sound fiscal reasoning to control cost and to strengthen those departments and services that are responsible for the financial viability of the institution. The results of this study show that our Respiratory Care Department has assumed the leadership role in the economic viability of our hospital and is its most cost-efficient contributor to health care.


Gadd45α activity is the principal effector of Shigella mitochondria-dependent epithelial cell death in vitro and ex vivo.
Modulation of death is a pathogen strategy to establish residence and promote survival in host cells and tissues. Shigella spp. are human pathogens that invade colonic mucosa, where they provoke lesions caused by their ability to manipulate the host cell responses. Shigella spp. induce various types of cell death in different cell populations. However, they are equally able to protect host cells from death. Here, we have investigated on the molecular mechanisms and cell effectors governing the balance between survival and death in epithelial cells infected with Shigella. To explore these aspects, we have exploited both, the HeLa cell invasion assay and a novel ex vivo human colon organ culture model of infection that mimics natural conditions of shigellosis. Our results definitely show that Shigella induces a rapid intrinsic apoptosis of infected cells, via mitochondrial depolarization and the ensuing caspase-9 activation. Moreover, for the first time we identify the eukaryotic stress-response factor growth arrest and DNA damage 45α as a key player in the induction of the apoptotic process elicited by Shigella in epithelial cells, revealing an unexplored role of this molecule in the course of infections sustained by invasive pathogens.


Pain Severity in Relation to Smoking Cessation Problems and Self-Efficacy for Quitting among Latinx Individuals Who Smoke Cigarettes: The Moderating Role of Perceived Discrimination.
Background: Latinx individuals experience significant tobacco cigarette smoking-related diseases and illnesses. Although most Latinx smokers report a desire to quit smoking, evidenced-based cessation treatments are underutilized in this group, which may partially be due to lower likelihood of receiving advice from a healthcare professional. Further, there are a lack of cessation treatments that account for comorbid symptoms/conditions (e.g., co-occurring pain) and social determinants of health (e.g., perceived discrimination). Extant work has established the reciprocal relation between pain and smoking trajectories. Additionally, although social determinants, such as perceived racial/ethnic discrimination, have demonstrated clinical relevance to a variety of health-related behaviors, limited work has examined the role of perceived discrimination in pain-smoking relations. The current study examined the effects of perceived discrimination and pain severity in relation to smoking cessation problems and self-efficacy for quitting among Latinx cigarette smokers. Method: Participants included 226 (Mage = 34.95 years, SD = 8.62; 38.5% female) adult Latinx daily cigarette smokers. Results: Results indicated that the interaction of pain and perceived discrimination was predictive of greater quit problems (p = 0.041) as well as greater confidence in the ability to refrain from smoking in response to internal (p < 0.001) and external stimuli (p < 0.001). Conclusions: Overall, this work provides a more nuanced understanding of the psychosocial contexts in which Latinx smokers may encounter problems related to quitting, and this data is important for future smoking cessation research and treatment.


Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis.
Parathyroid hormone (PTH) is the major hormonal regulator of calcium homeostasis. PTH is a potent stimulator of bone formation and can restore bone to an osteopenic skeleton, when administered intermittently. Osteoblasts are the primary target cells for the anabolic effects of PTH in bone tissue. Anabolic effects of PTH on bone have been demonstrated in animals and humans, by numerous measurement techniques including bone mineral density and bone histomorphometry. Clinically, the most important aspect of treatment for osteoporosis is prevention of fractures. Microstructural alterations, such as loss of trabecular connectivity, have been implicated in increased propensity for fracture. Recent two-dimensional (2D) and three-dimensional (3D) assessments of cancellous bone structure have shown that PTH can re-establish lost trabecular connectivity in animals and humans. These results provide new insight into the positive clinical effects of PTH in osteoporosis. In recent randomized controlled clinical trials of intermittent PTH treatment, PTH decreased incidence of vertebral and non-vertebral fractures in postmenopausal women. Thus, PTH shows strong potential as therapy for osteoporosis. However, 2D and 3D structural analysis of advanced osteopenia in animals has shown that there is a critical limit of trabecular connectivity and bone strength below which PTH cannot completely reverse the condition. Given that PTH treatment fails to completely restore trabecular connectivity and bone strength in animals with advanced osteopenia, early treatment of osteoporosis appears important and efficacious for preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.


Current concepts of browpexy.
The excess skin of the upper lid is not uncommonly secondary to the ptosis of the eyebrows. Blepharoplasty not only fails to correct this deformity but, in fact, may aggravate the sagging of the eyebrow, imparting a sad and elderly appearance to the face. A gracefully arching eyebrow at or slightly above the supraorbital rim renders the face more alert and beautiful. Of many procedures described, three browpexy techniques have withstood the test of time, each with its own set of advantages and limitations: (1) direct, (2) midforehead, and (3) frontal lift. Particular emphasis is given to the coronal-type forehead lift which, in addition to browpexy, can deal with the ptosis of the forehead, transverse forehead wrinkles, and glabellar rhytids.


Chemical composition, ensiling characteristics, and apparent digestibility of summer annual forages in a subtropical double-cropping system with annual ryegrass.
A 2-yr study was conducted to determine the chemical composition and digestibility of silages made from forage sorghum, pearl millet, and tropical corn managed to optimize forage quality. Silages were ensiled in upright concrete silos lined with plastic and fed to heifers to determine in vivo apparent digestibility. Samples were collected before and after ensiling to determine ensiling characteristics and forage quality. After ensiling, tropical corn had the greatest dry matter (DM), the lowest crude protein, and the greatest water-soluble concentrations. Tropical corn silage had a pH of 3.96. The pH of forage sorghum silage was 4.09, and pearl millet had a pH of 4.50. Pearl millet had the lowest concentration of preensiled water-soluble carbohydrate, which likely caused the high pH in the silage. There were no differences among the forages in DM loss during ensiling in yr 2. Heifers fed pearl millet silage consumed more DM, but digestible DM intake was not different among the three groups of heifers. The results of this experiment indicate that pearl millet would be less desirable as a crop intended solely for silage production. Both forage sorghum and tropical corn could be grown specifically for ensiling based on DM digestibility. The decision on which crop to use should be based on factors such as production costs, forage yields, and local growing conditions rather than silage quality.


Monoclonal antibody to acetylcholine receptor: cell line established from thymus of patient with Myasthenia gravis.
A human B cell line producing a monoclonal antibody to an antigenic determinant of acetylcholine receptors was established by cloning B cells that had been transformed in vitro by Epstein-Barr virus. The B cells were obtained from the thymus of a patient with myasthenia gravis. The antibody produced by the cell line precipitated acetylcholine receptors from denervated and innervated rat muscle and from human muscle, but did not show detectable response to the acetylcholine receptors from the electric organs of Narke japonica. The monoclonal antibody showed identical binding patterns in innervated and denervated rat muscles. Passive transfer of the monoclonal antibody into rats induced moderate muscle weakness and electromyographic changes characteristic of myasthenia gravis.


Fractional Flow Reserve: Patient Selection and Perspectives.
The aim of this review was to discuss the current practice and patient selection for invasive FFR, new techniques to estimate invasive FFR and future of coronary physiology tests. We elaborate on the indication and application of FFR and on the contraindications and concerns in certain patient populations.


Exposure of Inuit in Greenland to organochlorines through the marine diet.
High organochlorine concentrations have been found among the Inuit in eastern Canada and in Greenland. The present study was undertaken to assess the exposure to organochlorines in relation to age, sex, and diet in a general population sample of Inuit from Greenland. Survey data and plasma concentrations of 14 polychlorinated biphenyl (PCB) congeners and 16 pesticides, including 5 toxaphene congeners, were recorded in a random population survey of 408 adult indigenous Greenlanders. In a two-stage design, the survey response rate was 66%, and 90% of those randomly selected for blood testing participated. This was equivalent to an overall response rate of 59%. The median plasma concentration of the sum of PCB congeners was 13.3 microg/L; the lipid-adjusted value was 2109 microg/kg. The PCB concentration was twice as high as among the Inuit of Nunavik, Canada, 25 times higher than in a control group from southern Canada, and several times higher than the values found in European studies. Concentrations were similarly elevated for all PCB congeners and pesticides. The PCB congener pattern was similar to previous observations from the eastern Canadian Arctic and Greenland. Concentrations showed statistically significant positive associations with age, marine diet, and male sex in multiple linear regression analyses. The exceptionally high plasma concentrations of several organochlorines among the Inuit of Greenland are attributed to a lifelong high intake of seafood, in particular marine mammals. Concentrations of PCB adjusted for the consumption of marine food increased until approximately 40 yr of age, which is equivalent to the birth cohorts of the early 1950s. The age pattern indicates that bioaccumulation of PCB started in the 1950s, which is a likely date for the introduction of the compounds into the Arctic environment.


[Various characteristics of the anti-restriction mechanism in bacteriophage T5].
Bacteriophage T5 is not confined by the restriction systems of the second type EcoRII and EcoRV. Bacteriophage T5 DNA is not modified by EcoRII and EcoRV methylases in vivo. The sites of recognition for restriction endonuclease EcoRV are mapped at 24.4; 57.6; 68.5; 70.2% of T5 DNA, while the sites at 5.1; 7.6% are recognized by EcoRII, the sites at 5.75; 6.0 and 6.5% are recognized by HpaI in FST. A high activity of restriction endonucleases EcoRI and EcoRV is demonstrated in crude extracts of E. coli B834 (RI) and E. coli B834 (RV) cells infected by bacteriophage T5. The simultaneous infection of E. coli B834 (RI) or E. coli B834 (RV) cells by the amber mutants of bacteriophage T5 and the suppressing phage lambda NM761 does not result in the protection of lambda DNA by the T5 anti-restriction mechanism. The presented data support the hypothesis that the anti-restriction mechanism of bacteriophage T5 is based on prevention of T5 DNA contacts with restriction enzymes by a specific phage protein.


The effect of hiatus hernia on gastro-oesophageal junction pressure.
Hiatus hernia and lower oesophageal sphincter hypotension are often viewed as opposing hypotheses for gastro-oesophageal junction incompetence. To examine the interaction between hiatus hernia and lower oesophageal sphincter hypotension. In seven normal subjects and seven patients with hiatus hernia, the squamocolumnar junction and intragastric margin of the gastro-oesophageal junction were marked with endoscopically placed clips. Axial and radial characteristics of the gastro-oesophageal junction high pressure zone were mapped relative to the hiatus and clips during concurrent fluoroscopy and manometry. Responses to inspiration and abdominal compression were also analysed. In normal individuals the squamocolumnar junction was 0.5 cm below the hiatus and the gastro-oesophageal junction high pressure zone extended 1.1 cm distal to that. In those with hiatus hernia, the gastro-oesophageal junction high pressure zone had two discrete segments, one proximal to the squamocolumnar junction and one distal, attributable to the extrinsic compression within the hiatal canal. Inspiration and abdominal compression mainly augmented the distal one. Simulation of hernia reduction by algebraically summing the proximal segment pressures with the hiatal canal pressures restored normal maximal pressure, radial asymmetry, and dynamic responses of the gastro-oesophageal junction. Hiatus hernia reduces lower oesophageal sphincter pressure and alters its dynamic responsiveness by spatially separating pressure components derived from the intrinsic lower oesophageal sphincter and the extrinsic compression of the oesophagus within the hiatal canal.


Machine Learning Accelerated, High Throughput, Multi-Objective Optimization of Multiprincipal Element Alloys.
Multiprincipal element alloys (MPEAs) have gained surging interest due to their exceptional properties unprecedented in traditional alloys. However, identifying an MPEA with desired properties from a huge compositional space via a cost-effective design remains a grand challenge. To address this challenge, the authors present a highly efficient design strategy of MPEAs through a coherent integration of molecular dynamics (MD) simulation, machine learning (ML) algorithms, and genetic algorithm (GA). The ML model can be effectively trained from 54 MD simulations to predict the stiffness and critical resolved shear stress (CRSS) of CoNiCrFeMn alloys with a relative error of 2.77% and 2.17%, respectively, with a 12 600-fold reduction of computation time. Furthermore, by combining the highly efficient ML model and a multi-objective GA, one can predict 100 optimal compositions of CoNiCrFeMn alloys with simultaneous high stiffness and CRSS, as verified by 100 000 ML-accelerated predictions. The highly efficient and precise design strategy can be readily adapted to identify MPEAs of other principal elements and thus substantially accelerate the discovery of other high-performance MPEA materials.


Canine distemper virus from diseased large felids: biological properties and phylogenetic relationships.
Specific pathogen free (SPF) domestic cats were inoculated with tissue homogenate obtained from a Chinese leopard (Panthera pardus japonensis) that had died in a North American zoo from a natural infection with canine distemper virus (CDV). The cats developed a transient cell-associated CDV viraemia along with pronounced lymphopenia but did not show any clinical symptoms. Plasma neutralizing-antibody titres against the homologous CDV (A92-27/4, isolated from the Chinese leopard) were consistently higher than against the CDV vaccine strain 'Bussell'. The Chinese leopard CDV isolate showed in vitro biological properties reminiscent of virulent, wild-type CDV strains. Sequence analysis of the H gene of two large felid CDV isolates from the USA (A92-27/4 and A92-6) revealed up to 10% amino acid changes including up to four additional potential N-linked glycosylation sites in the extra-cytoplasmic domain as compared to CDV vaccine strains. Phylogenetic analysis was performed using the entire coding region of the H gene and a 388 bp fragment of the P gene of several morbillivirus species. Evidence was obtained that recent CDV isolates from different species in the United States (including isolates from large felids), Europe and Africa are significantly distinct from CDV vaccine strains. All wild-type CDV isolates analysed clustered according to geographical distribution rather than to host species origin. By sequence analysis a CDV epizootic among large felids in a Californian safari park was linked to a virus which most likely originated from feral non-felid carnivores.


Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation.
Diltiazem (DTZ) N-demethylation occurs by cytochrome P-450 (CYP) 3A based on the following observations: 1) a single enzyme Michaelis-Menten model of metabolite formation, 2) high correlations of DTZ N-demethylation activity to other CYP3A activities, 3) inhibition of DTZ N-demethylation activity by triacetyloleandomycin, and 4) DTZ N-demethylation activity by expressed CYP3A enzymes only. The mean K(m)s for DTZ N-demethylation in human liver microsomes and expressed CYP3A4(+b(5)) were 53 and 16 microM, respectively. A 30-min preincubation of DTZ in expressed CYPs inhibited CYP3A4(+b(5)) by 100%, of which 55% was due to formation of a metabolite intermediate complex (MIC), which is an inactive form of CYP. MIC was observed in human liver microsomes and cDNA-expressed CYP3A only. In experiments to assess simultaneous MIC formation and loss of CYP3A activity, DTZ caused greater than 80% inhibition of midazolam hydroxylation after a 60-min preincubation in human liver microsomes. The rate constants for MIC formation and loss of midazolam hydroxylation activity were equivalent for the line of best fit for both data sets, which illustrates that MIC formation causes the inhibition of CYP3A activity. The mechanistic inhibition was characterized in expressed CYP3A4(+b(5)), which exhibited a concentration-dependent formation of MIC by DTZ (1-100 microM) with an estimated k(inact) of 0.17 min(-1) and K(I) of 2.2 microM. The partition ratio for expressed CYP3A4(+b(5)) was substrate concentration dependent and varied from 13 to 86. This study showed that DTZ inhibition of CYP3A substrate metabolism occurs primarily by MIC formation.


The proteins and RNAs of St. Abb's Head virus, a Scottish Uukuvirus.
The proteins and RNAs of St. Abb's Head virus have been analysed, and were found to be characteristic of the Uukuvirus genus of the family Bunyaviridae. Two glycoproteins, G1 and G2 (mol. wt. 62K and 75K), and a nucleocapsid protein, N (mol. wt. 25K), were detected in infected cells by immunoprecipitation; the synthesis of N preceded the synthesis of G1 and G2. The glycoproteins were relatively cysteine-rich compared to the N protein, and the unglycosylated forms of G1 and G2 (using the inhibitor tunicamycin) had a mol. wt. of about 58K. Translation in vitro of mRNA from infected cells gave two immunoprecipitable products which are thought to be equivalent to N and G1/G2. Three RNA species were found in St. Abb's Head virus nucleocapsids, and were estimated to be 8500 bases (L), 3600 bases (M) and 1900 bases (S) in length. At least one additional virus-specific RNA species was detected in infected cells. The similarity between the proteins and RNAs of St. Abb's Head virus and Uukuniemi virus (the prototype of the genus) is discussed.


AMINO ACIDS RELEASED FROM THE CEREBRAL CORTEX IN RELATION TO ITS STATE OF ACTIVATION.
The rate of release of gamma-aminobutyric acid from the perforated pial surface of the cerebral cortex in the cat showed systematic variations with the state of activation or "arousal" of the electrocorticogram. In animals subjected to midbrain coagulation and showing constant spindle patterns characteristic of sleep, the rate of release was three times greater (about 2 micrograms per hour per square centimeter) than in animals showing a largely "aroused" electrocorticogram, which had sections of the upper cervical cord or were neuraxially intact but had been given local anesthesia. The rate of release of glutamic acid was lower in the "sleeping" animals than in "aroused" animals, while no such differences were found for glutamine and aspartic acid. Such studies may lead to a better understanding of chemical mechanisms involved in the control of states of consciousness by the brain stem.


Diffusive exchange of PAHs across the air-water interface of the Kaohsiung Harbor lagoon, Taiwan.
Instantaneous air-water polycyclic aromatic hydrocarbons (PAHs) exchange fluxes were calculated in 22 pairs of ambient air and water samples from Kaohsiung Harbor lagoon, from December 2003 to January 2005. The highest net volatilization (3135 ng m(-2) day(-1)) and absorptive (-1150 ng m(-2) day(-1)) fluxes in the present study were obtained for the three-ring PAH phenanthrene on 7 April and 27 January 2004, respectively. All PAH diffusive fluxes for three-ring PAHs except phenanthrene were mainly volatilization exchange across the air-water interface. Phenanthrene and the four-ring PAHs were absorbed primarily from the atmosphere and deposited to the surface water, although some minor volatilization fluxes were also observed. Differences in flux magnitude and direction between the dry and wet seasons were also evident for PAHs. Strong absorptive/weaker volatilization PAH fluxes occurred in the dry season, but the opposite was found in the wet season. The mean daily PAH diffusive fluxes were an in flux of -635 ng m(-2) day(-1) in the dry season and an efflux of 686 ng m(-2) day(-1) in the wet season. The integrated absorbed and emitted fluxes of PAHs for harbor lagoon surface waters in the dry and wet seasons were 3.1 kg and 3.4 kg, respectively. Different from water bodies located in temperate zone, phenanthrene diffusive fluxes in Kaohsiung Harbor lagoon was favored in volatilization from surface waters during the wet season (April to September) because of scavenging by precipitation and dilution by prevailing southwesterly winds. In addition, this study used both of salinity and temperature to improve estimation of Henry's law constants (H) of PAHs in a tropical coastal area and show that correction for salinity produced 13-15% of differences in H values.


The clinical relevance of gene expression based prognostic signatures in colorectal cancer.
Colorectal cancer (CRC) is one of the most prevalent cancers, with more than one million new cases every year. In the last few decades, several advancements in therapeutic and preventative levels have reduced the mortality rate, but new biomarkers are required for improved prognosis. The alterations at the genetic and epigenetic level have been recognized as major players in tumorigenesis. The products of gene expression in the form of mRNA, microRNA, and long-noncoding RNA, have started to emerge as important regulatory molecules, playing an important role in cancer. Gene-expression based prognostic risk scores, which quantify and compare their expression, have emerged as promising biomarkers with enormous clinical value. These composite multi-gene models in which more than one gene is used to predict prognosis have been shown to be significantly effective in identifying patients with multiple clinico-pathological risks like overall mortality, response to chemotherapy, risk of metastasis, etc. The advent of microarray and advanced sequencing technologies have led to the generation of large datasets like TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), which have fueled the search for new biomarkers. Continuous evaluation of these candidate biomarkers in clinical settings is promising to improve the management of CRC. These composite gene signatures provide potential in identifying high-risk patients, which might help clinicians to better manage these patients and design appropriate personalized therapeutic interventions. In this review, we emphasize on composite prognostic scores from diverse resources with clinical utility in CRC.


Serum CRP interacts with SPARC and regulate immune response in severe cases of COVID-19 infection.
Serum C-reactive protein (CRP) has been found elevated during COVID-19 infection, and associated with systematic inflammation as well as a poor clinical outcome. However, how did CRP participated in the COVID-19 pathogenesis remains poorly understood. Here, we report that serum C-reactive protein (CRP) levels are correlated with megakaryocyte marker genes and could regulate immune response through interaction with megakaryocytes. Molecular dynamics simulation through ColabFold showed a reliable interaction between monomeric form of CRP (mCRP) and the secreted protein acidic and rich in cysteine (SPARC). The interaction does not affect the physiological activities of SPARC while would be disturbed by pentamerization of CRP. Interplay between SPARC and mCRP results in a more intense immune response which may led to poor prognosis. This study highlights the complex interplay between inflammatory markers, megakaryocytes, and immune regulation in COVID-19 and sheds light on potential therapeutic targets.


[Quantitative analysis of the cellular ultrastructure of infiltrative breast cancer].
Cataplasia staging was carried out with the aid of a morphometric study of cell ultrastructure of 45 infiltrative breast cancers. A coefficient describing the free polyribosome structure proved to be of the greatest predictive value, its magnitude and cataplasia degree being connected by a direct relationship. Many theoretical errors may be avoided due to application of quantitative methods of electron microscopy.


Database and new models based on a group contribution method to predict the refractive index of ionic liquids.
Refractive index is one of the important physical properties, which is widely used in separation and purification. In this study, the refractive index data of ILs were collected to establish a comprehensive database, which included about 2138 pieces of data from 1996 to 2014. The Group Contribution-Artificial Neural Network (GC-ANN) model and Group Contribution (GC) method were employed to predict the refractive index of ILs at different temperatures from 283.15 K to 368.15 K. Average absolute relative deviations (AARD) of the GC-ANN model and the GC method were 0.179% and 0.628%, respectively. The results showed that a GC-ANN model provided an effective way to estimate the refractive index of ILs, whereas the GC method was simple and extensive. In summary, both of the models were accurate and efficient approaches for estimating refractive indices of ILs.


Genomic evidence of human selection on Vavilovian mimicry.
Vavilovian mimicry is an evolutionary process by which weeds evolve to resemble domesticated crop plants and is thought to be the result of unintentional selection by humans. Unravelling its molecular mechanisms will extend our knowledge of mimicry and contribute to our understanding of the origin and evolution of agricultural weeds, an important component of crop biology. To this end, we compared mimetic and non-mimetic populations of Echinochloa crus-galli from the Yangtze River basin phenotypically and by genome resequencing, and we show that this weed in rice paddies has evolved a small tiller angle, allowing it to phenocopy cultivated rice at the seedling stage. We demonstrate that mimetic lines evolved from the non-mimetic population as recently as 1,000 yr ago and were subject to a genetic bottleneck, and that genomic regions containing 87 putative plant architecture-related genes (including LAZY1, a key gene controlling plant tiller angle) were under selection during the mimicry process. Our data provide genome-level evidence for the action of human selection on Vavilovian mimicry.


Cervical muscle afferents play a dominant role over vestibular afferents during bilateral vibration of neck muscles.
A previous study showed that vibratory stimulation of neck muscles in humans induced short-latency electromyographic (EMG) activation of lower leg muscles, producing postural reactions at the feet. These findings indicated that cervical proprioception contributes to stabilization of stance through rapidly integrated pathways. However, as vibration may excite both proprioceptive and vestibular afferents, and because of the proximity of neck muscles to the vestibular apparatus, neck muscle vibration could also have activated the vestibular system thereby contributing to the effect observed. To investigate any possible contribution of vestibular stimulation, vibratory stimuli were applied bilaterally and separately to the splenius muscles of the neck and the planum mastoideum overlying the vestibular organs. Ten normal subjects, with eyes closed, were exposed to vibratory stimulation of two different amplitudes and frequencies. Responses were assessed by EMG activity recorded from tibialis anterior and gastrocnemius muscles of both legs and by changes in center of pressure as measured by a force platform. Results indicated that vibration induced reproducible EMG and postural responses in the anteroposterior direction, particularly on cessation of vibration. EMG and postural responses were considerably lower and less consistent with mastoid vibration compared with neck muscles vibration. Previous reports suggest that vibratory stimulation could propagate to the vestibular organs and generate a vestibular-induced postural activation. However, our findings indicate that cervical muscles afferents play a dominant role over vestibular afferents when vibration is directed towards the neck muscles.


Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
ABI-007 is a novel Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of Cremophor EL may permit ABI-007 to be administered without the premedications used routinely for the prevention of hypersensitivity reactions. Furthermore, this novel formulation permits a higher paclitaxel concentration in solution and, thus, a decreased infusion volume and time. This Phase I study examines the toxicity profile, maximum tolerated dose (MTD), and pharmacokinetics of ABI-007. ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies. Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel C(max) and area under the curve(inf) values to increase linearly over the ABI-007 dose range of 135-300 mg/m2. C(max) and area under the curve(inf) values for individual patients correlated well with toxicity. ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.


MUC2 is the prominent colonic mucin expressed in ulcerative colitis.
It has been shown that MUC2 is the prominent mucin synthesised in healthy colon. To identify the predominant mucins in ulcerative colitis (UC) and to study their biosynthesis. Mucin was purified from UC resection specimens. This mucin on sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) presented as one, high molecular weight, periodic acid/Schiff's reagent (PAS) stainable band. Amino acid composition showed a close resemblance to that of MUC2. Immunoprecipitation with a specific anti-MUC2 antiserum confirmed that this mucin was MUC2. In addition, on the mRNA level MUC2 was also the most prominent mucin expressed in UC. Polyclonal antiserum was elicited, mainly recognising mucin peptide epitopes of UC and normal colonic mucin. Biosynthetic studies with [35S]amino acids showed that the MUC2-precursor in UC displayed a molecular mass on SDS-PAGE of approximately 600 kDa. This precursor was converted into a mature MUC2 with anomalous mobility on SDS-PAGE of 550 kDa and was secreted. Only this 550 kDa band could be labelled with [35S]sulphate and stained by PAS. This study shows that in parallel with the mucin expression in healthy controls, MUC2 is the major mucin expressed in UC. Qualitatively, MUC2 biosynthesis seems unchanged in UC.


Diabetic nephropathy - is this an immune disorder?
Chronic diabetes is associated with metabolic and haemodynamic stresses which can facilitate modifications to DNA, proteins and lipids, induce cellular dysfunction and damage, and stimulate inflammatory and fibrotic responses which lead to various types of renal injury. Approximately 30-40% of patients with diabetes develop nephropathy and this renal injury normally progresses in about a third of patients. Due to the growing incidence of diabetes, diabetic nephropathy is now the main cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence from experimental and clinical studies has demonstrated that renal inflammation plays a critical role in determining whether renal injury progresses during diabetes. However, the immune response associated with diabetic nephropathy is considerably different to that seen in autoimmune kidney diseases or in acute kidney injury arising from episodes of ischaemia or infection. This review evaluates the role of the immune system in the development of diabetic nephropathy, including the specific contributions of leucocyte subsets (macrophages, neutrophils, mast cells, T and B lymphocytes), danger-associated molecular patterns (DAMPs), inflammasomes, immunoglobulin and complement. It also examines factors which may influence the development of the immune response, including genetic factors and exposure to other kidney insults. In addition, this review discusses therapies which are currently under development for targeting the immune system in diabetic nephropathy and indicates those which have proceeded into clinical trials.


Recent water quality trends in the Schuylkill River, Pennsylvania, USA: a preliminary assessment of the relative influences of climate, river discharge and suburban development.
Climate, flow rate and land use are all known drivers of water quality in river systems, but determining the relative influences of these factors remains a significant challenge for aquatic science and management. Long-term data from the Schuylkill River at Philadelphia is assessed here in an attempt to ascertain the separate and combined influence of these major drivers on water quality in a developed watershed. Water quality measures including nutrients, conservative solutes and bacteria all elicited distinct seasonal patterns driven primarily by river discharge. Mass transport rates of sodium and chloride have increased with time, and were elevated in winter, presumably as a function of road salt deposition. A steady increase in developed land area in the watershed has occurred in recent decades, which allowed the use of time as a surrogate parameter for regional development in the construction of multiple factor linear models predicting the relative influences of precipitation, river discharge and developed land area on river water quality. Linear models predicting annually averaged water quality measures showed the effects of precipitation, discharge and developed land area to be of nearly equal importance in regulating levels of conductivity, alkalinity, sodium, and chloride in the river. Models predicting water quality variables for discrete samples demonstrated that river flow was the major determinant of daily variability in alkalinity, conductivity, hardness and calcium levels, while still resolving the highly significant influence of watershed development on water quality. Increases in solute transport in the Schuylkill River in recent decades appear to be the direct result of modern suburban development in the watershed.


Adherence Patterns and Dose Response of Physiotherapy for Rotator Cuff Pathology: Longitudinal Cohort Study.
Physiotherapy is considered to be essential for the successful operative and nonoperative management of rotator cuff pathology; however, the extent to which patients adhere to assigned physiotherapy activities and how this impacts recovery is unknown. The purpose of this study was to measure the rate and patterns of participation in physiotherapy for rotator cuff disorders, assess the dose response between physiotherapy activity and recovery, and explore patient factors predictive of physiotherapy participation. We report a prospective longitudinal study of 42 patients undergoing physiotherapy for symptomatic rotator cuff pathology. The patients were issued a smartwatch that recorded inertial sensor data while they performed physiotherapy exercises both in the clinic and in the home setting. A machine learning approach was used to assess total physiotherapy participation from smartwatch inertial data. Primary outcomes were the Disabilities of the Arm Shoulder and Hand and numeric pain rating scale assessed every 4 weeks until 12 weeks follow-up. The relationships between participation, outcomes, and clinical patient variables were assessed in univariable analyses. Mean physiotherapy exercise participation in clinic and at home were 11 minutes per week and 33 minutes per week, respectively, with patients participating in physiotherapy on 41% of days assigned to treatment. Home physiotherapy participation decreased significantly over time (P=.03). There was a statistically significant and clinically meaningful relationship between cumulative physiotherapy participation and recovery demonstrated by pain scores at 8 weeks (P=.02) and 12 weeks (P=.05) and disability scores at 8 weeks (P=.04) and 12 weeks (P=.04). Low patient expectations and self-efficacy were associated with low rates of physiotherapy participation. There was a low rate of participation in home shoulder physiotherapy exercise, and a statistically and clinically significant dose response of physiotherapy on treatment outcome in patients with rotator cuff pathology. The findings highlight the opportunity to develop novel methods and strategies to improve the participation in and efficacy of physiotherapy exercises for rotator cuff disorders. RR2-10.2196/17841.


Conformational changes in gastric H+/K+-ATPase monitored by difference Fourier-transform infrared spectroscopy and hydrogen/deuterium exchange.
Gastric H+/K+-ATPase is a P-type ATPase responsible for acid secretion in the stomach. This protein adopts mainly two conformations called E1 and E2. Even though two high-resolution structures for a P-ATPase in these conformations are available, little structural information is available about the transition between these two conformations. In the present study, we used two experimental approaches to investigate the structural differences that occur when gastric ATPase is placed in the presence of various ligands and ligand combinations. We used attenuated total reflection-Fourier-transform IR experiments under a flowing buffer to modify the environment of the protein inside the measurement cell. The high accuracy of the results allowed us to demonstrate that the E1-E2 transition induces a net change in the secondary structure that concerns 10-15 amino acid residues of a total of 1324 in the proteins. The E2.K+ structure is characterized by a decreased beta-sheet content and an increase in the disordered structure content with respect to the E1 form of the enzyme. Modifications in the absorption of the side chain of amino acids are also suggested. By using hydrogen/deuterium-exchange kinetics, we show that tertiary-structure modifications occurred in the presence of the same ligands, but these changes involved several hundreds of residues. The present study suggests that conformational changes in the catalytic cycle imply secondary-structure rearrangements of small hinge regions that have an impact on large domain re-organizations.


Decrease in early mortality for newly diagnosed multiple myeloma patients in the Netherlands: a population-based study.
Identification of risk factors for early mortality (EM) in multiple myeloma (MM) patients may contribute to different therapeutic approaches in patients at risk for EM. This population-based study aimed to assess trends in EM and risk factors for EM among MM patients diagnosed in the Netherlands. All MM patients, newly diagnosed between 1989 and 2018, were identified in the Netherlands Cancer Registry. Patients were categorized into three calendar periods (1989-1998, 1999-2008, 2009-2018) and into five age groups (≤65, 66-70, 71-75, 76-80, >80 years). EM was defined as death by any cause ≤180 days post-diagnosis. We included 28,328 MM patients (median age 70 years; 55% males). EM decreased from 22% for patients diagnosed in 1989-1998 to 13% for patients diagnosed in 2009-2018 (P < 0.01) and this decrease was observed among all age groups. Exact causes of death could not be elucidated. Besides patient's age, we found that features related to a more aggressive disease presentation, and patient characteristics reflecting patients' physical condition were predictive of EM. In summary, EM decreased from 1999 onwards. Nevertheless, EM remains high, especially for patients aged >70 years. Therefore, novel strategies should be explored to improve the outcome of patients at risk for EM.


Evaluating "mentalizing positive affect" as an intervention for enhancing positive affectivity in borderline personality disorder using a single-case multiple-baseline design.
Evidence-based treatments for borderline personality disorder (BPD), including mentalization-based treatment (MBT), have not adequately examined changes in positive affect (PA) in the treatment of BPD. Therefore, we developed a new intervention, "mentalizing positive affect," and evaluated its effect on PA, negative affect, BPD severity, ego-resiliency, and quality of life during MBT treatment for BPD. In a single-case multiple-baseline design, 4 female BPD patients received 6 months of individual MBT, after which they were followed up for 2 months. Intensive repeated measurements data were subjected to hierarchical linear modeling to analyze whether the positive intervention was related to changes in self-reported outcome measures. Our results failed to support a co-occurring increase in the reporting of PA related to the "mentalizing positive affect" intervention. However, the slope of PA increased at a quicker rate after the end of treatment, perhaps indicating a delayed treatment effect. "Mentalizing positive affect" was related to a marginally significant decrease in the mean level of BPD severity compared with standard MBT. Moreover, focusing on PA in MBT seemed feasible for maintaining a good working alliance. Our findings call for more research to test interventions aimed at enhancing PA in the treatment of BPD. Such efforts might well involve treatment of longer duration and higher intensity to increase the number of sessions, as well as longer follow-up periods, than we used. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Cortical thickness in major depressive disorder: A systematic review and meta-analysis.
Neuroimaging studies assessing neurobiological differences between patients with major depressive disorder (MDD) and healthy controls (HC) are often hindered by small sample sizes and heterogeneity of the patient sample. We performed a comprehensive literature search for studies assessing cortical thickness between patient and control groups, including studies investigating treatment effects on cortical thickness. We identified 34 studies meeting criteria for the systematic review and used Seed-based d Mapping to meta-analyze 24 of those that met additional criteria. Analysis of the full sample of subjects (MDD = 1073; HC = 936) revealed significant thinning in the MDD group in the bilateral orbitofrontal gyrus (BA 11), left pars opercularis (BA 45) and left calcarine fissure/lingual gyrus (BA 17), as well as an area of significant thickening in the left supramarginal gyrus (BA 40). These results support other imaging modalities that report disruptions in various frontal and temporal areas in MDD and identify additional areas in all major cerebral lobes likely to be significant when parsing for biomarkers of treatment or relapse.


Mood impairment is stronger in young than in older adults after sleep deprivation.
Sleep deprivation commonly impairs affective regulation and causes worse mood. However, the majority of previous research concerns young adults. Because susceptibility to sleep deprivation and emotion regulation change distinctively across adult age, we tested here the hypothesis that the effect of sleep deprivation on mood is stronger in young than in older adults. In an experimental design, young (18-30 years) and older adults (60-72 years) participated in either a sleep control (young, n = 63; older, n = 47) or a total sleep deprivation condition (young, n = 61; older, n = 47). Sleepiness, mood and common symptoms of sleep deprivation were measured using established questionnaires and ratings. Sleep-deprived participants felt more sleepy, stressed and cold, and reported lower vigour and positive affect, regardless of age. All the other outcome measures (negative affect, depression, confusion, tension, anger, fatigue, total mood disturbance, hunger, cognitive attenuation, irritability) showed a weaker response to sleep deprivation in the older group, as indicated by age*sleep deprivation interactions (ps < 0.05). The results show that older adults are emotionally less affected by sleep deprivation than young adults. This tolerance was mainly related to an attenuated increase in negative mood. This could possibly be related to the well-known positivity effect, which suggests that older adults prioritize regulating their emotions to optimize well-being. The results also highlight that caution is warranted when generalizing results from sleep deprivation studies across the adult lifespan.


Transdiagnostic biomarkers of mental illness across the lifespan: A systematic review examining the genetic and neural correlates of latent transdiagnostic dimensions of psychopathology in the general population.
This systematic review synthesizes evidence from research investigating the biological correlates of latent transdiagnostic dimensions of psychopathology (e.g., the p-factor, internalizing, externalizing) across the lifespan. Eligibility criteria captured genomic and neuroimaging studies investigating general and/or specific dimensions in general population samples across all age groups. MEDLINE, Embase, and PsycINFO were searched for relevant studies published up to March 2023 and 46 studies were selected for inclusion. The results revealed several biological correlates consistently associated with transdiagnostic dimensions of psychopathology, including polygenic scores for ADHD and neuroticism, global surface area and global gray matter volume. Shared and unique associations between symptom dimensions are highlighted, as are potential age-specific differences in biological associations. Findings are interpreted with reference to key methodological differences across studies. The included studies provide compelling evidence that the general dimension of psychopathology reflects common underlying genetic and neurobiological vulnerabilities that are shared across diverse manifestations of mental illness. Substantive interpretations of general psychopathology in the context of genetic and neurobiological evidence are discussed.


Absorption efficiency enhancement in inorganic and organic thin film solar cells via plasmonic honeycomb nanoantenna arrays.
We demonstrate theoretically that by embedding plasmonic honeycomb nanoantenna arrays into the active layers of inorganic (c-Si) and organic (P3HT:PCBM/PEDOT:PSS) thin film solar cells, absorption efficiency can be improved. To obtain the solar cell absorption spectrum that conforms to the solar radiation, spectral broadening is achieved by breaking the symmetry within the Wigner-Seitz unit cell on a uniform hexagonal grid. For optimized honeycomb designs, absorption efficiency enhancements of 106.2% and 20.8% are achieved for c-Si and P3HT:PCBM/PEDOT:PSS thin film solar cells, respectively. We have demonstrated that the transverse modes are responsible for the enhancement in c-Si solar cells, whereas both the longitudinal and transverse modes, albeit weaker, are the main enhancement mechanisms for P3HT:PCBM/PEDOT:PSS solar cells. For both inorganic and organic solar cells, the absorption enhancement is independent of polarization.


Müllerian agenesis: etiology, diagnosis, and management.
Mullerian agenesis, a congenital malformation of the genital tract is the second most common cause of primary amenorrhea. Its etiology is poorly understood but it may be associated with renal, skeletal, and other abnormalities. The diagnosis is often made either radiologically or laparoscopically in patients in whom hormonal and karyotypic investigations for primary amenorrhea are normal. Two-dimensional ultrasound is not a reliable method of diagnosis, as exemplified by the two cases presented in this review; however, three-dimensional ultrasound may be a more sensitive diagnostic tool. The management is varied, but we conclude that the treatment of choice should be a nonsurgical approach aimed at creating a neovagina. Because of the implications for reproduction, these patients require psychological support, which should be offered as part of therapy. Gynecologists and Family Physicians After completion of this article, the reader will be able to describe the pathophysiology and clinical presentation of mülerian agenesis and to list the other abnormalities associated with this condition and to outline potential treatment options for a patient with müllerian agenesis.


Estimating time-varying exposure-outcome associations using case-control data: logistic and case-cohort analyses.
Traditional analyses of standard case-control studies using logistic regression do not allow estimation of time-varying associations between exposures and the outcome. We present two approaches which allow this. The motivation is a study of vaccine efficacy as a function of time since vaccination. Our first approach is to estimate time-varying exposure-outcome associations by fitting a series of logistic regressions within successive time periods, reusing controls across periods. Our second approach treats the case-control sample as a case-cohort study, with the controls forming the subcohort. In the case-cohort analysis, controls contribute information at all times they are at risk. Extensions allow left truncation, frequency matching and, using the case-cohort analysis, time-varying exposures. Simulations are used to investigate the methods. The simulation results show that both methods give correct estimates of time-varying effects of exposures using standard case-control data. Using the logistic approach there are efficiency gains by reusing controls over time and care should be taken over the definition of controls within time periods. However, using the case-cohort analysis there is no ambiguity over the definition of controls. The performance of the two analyses is very similar when controls are used most efficiently under the logistic approach. Using our methods, case-control studies can be used to estimate time-varying exposure-outcome associations where they may not previously have been considered. The case-cohort analysis has several advantages, including that it allows estimation of time-varying associations as a continuous function of time, while the logistic regression approach is restricted to assuming a step function form for the time-varying association.


The multifactorial etiology of graft-versus-host disease.
Graft-versus-host disease (GVHD), a major complication of bone marrow transplantation, often occurs despite genotypic HLA identity between patient and donor. Here, Gijsbert de Gast and his colleagues suggest that pretransplant cytoreductive therapy reactives latent virus and protozoan infections and promotes the invasion of bacteria and fungi through damaged mucosal membranes. Mature donor T cells sensitized to microbial antigens produce gamma interferon that induces the expression of HLA class II antigens. Non-HLA antigens are presented in conjunction with HLA class II antigens and stimulate graft-versus-host reactions against non-HLA antigens expressed on the target cells.


Gestational Trophoblastic Disease - Clinicopathological Study at Tertiary Care Hospital.
Gestational Trophoblastic Disease (GTD) is a term used for a group of pregnancy-related tumours. These consist of various tumours and tumour like lesions characterized by proliferation of trophoblastic tissue. Amongst GTD, hydatidiform moles are the most common form. These lesions sometimes may develop into invasive moles, or, in rare cases, into choriocarcinoma. To study the clinicopathologic characteristics and prevalence of different forms of gestational trophoblastic disease in a tertiary care hospital. The present study was descriptive, observational, analytical type done in Department of Pathology at tertiary care hospital from May 2012 to April 2016. All cases clinically suspected of GTD were included and confirmation was done by histopathological study on H&E stained slides. The cases of GTD were classified according to WHO classification. Detailed histomorphological features and beta human Chorionic Gonadotropin (hCG) levels were correlated. During study period, 18345 deliveries were reported; out of which 77 cases were diagnosed as GTD. Almost 97.40% cases were of hydatidiform moles, 1.30% cases of choriocarcinoma and 1.30% cases of Placental Site Trophoblastic Tumour (PSTT). Among the cases of hydatidiform mole 57.34% were complete mole and 41.33% cases were of partial mole. The common clinical presentation was per vaginal bleeding and amenorrhea. The blood group A was most commonly observed in patient (49.35%). In majority of cases beta hCG levels were between 50,000 to 100000 mIU/ml. The correlation between beta hCG level and GTD were done. Pregnant females clinically presenting with abnormal vaginal bleeding must be evaluated for GTD. Histopathological examination is helpful for confirmatory diagnosis. Follow up of such patients is essential for early detection of malignant trophoblastic tumours.


Adherence to guidelines for drug treatment of asthma in children: potential for improvement in Swedish primary care.
Adherence to guidelines in general is poor. Because asthma is the most common chronic disease in Swedish children, identifying areas for improvement regarding drug treatment for asthma is crucial. To explore the utilisation patterns of anti-asthmatic drugs in children with asthma in relation to evidence-based guidelines. All children visiting 14 primary healthcare centres in Stockholm, Sweden, who had their first prescription of anti-asthmatic agents dispensed between July 2006 and June 2007 were followed over 24 consecutive months. The children (1033 in total) were divided in two age groups: 0-6 years and 7-16 years. The outcome measurements were: the characteristics of the physicians initiating drug treatment; the extent to which the children were initiated on the drugs recommended in the guidelines; and the amount and frequency of drugs dispensed over time and whether the dosage texts on the prescriptions contained adequate information. In 54% of the older children and 35% of the younger children, only one prescription for anti-asthmatic drugs was dispensed during two years of follow-up following the first prescription. In school-aged children, 50% were initiated on inhaled short-acting bronchodilating beta2-agonists (SABA) in monotherapy. Among preschool children, 64% were initiated on SABA and inhaled corticosteroids in combination. In 41% of the prescriptions dispensed, the indication was stated and in 25% the mechanism of action was stated. Drug therapy was initiated by a general practitioner in 42% of the younger children and 72% of the older children. There is a need for improvement in adherence to guidelines in important areas. Asthma, especially among children aged 7-16 years, is usually a chronic disease and should, in many cases, be treated with anti-asthmatics counteracting inflammation. However, this was not the case in our study. In addition, the dosage texts written by the physicians did not follow recommendations and may negatively influence patient safety.


The role of culture, family processes, and anger regulation in Korean American adolescents' adjustment problems.
Using an ecologically informed, developmental psychopathology perspective, the present study examined contextual and intrapersonal predictors of depressive symptoms and externalizing problems among Korean American adolescents. Specifically, the role of cultural context (self-construals), family processes (family cohesion and conflict), and anger regulation (anger control, anger suppression, and outward anger expression) were examined. Study participants were N = 166 Korean American adolescents ranging from 11 to 15 years old (M = 13.0, SD = 1.2). Results showed that depressive symptoms were significantly associated with lower levels of perceived family cohesion, higher levels of perceived family conflict intensity, and higher levels of anger suppression. Externalizing problems were associated with male gender, a weaker interdependent self-construal, higher levels of perceived family conflict, lower levels of anger control, and higher levels of outward anger expression. The distinction between specific versus common factors associated with depressive symptoms and externalizing problems was discussed with an eye toward prevention or intervention strategies targeting specific coping mechanisms (e.g., generating alternatives to anger suppression) or developing psychoeducational approaches to facilitate family processes.


Shedding Light on Colorectal Cancer: An In Vivo Raman Spectroscopy Approach Combined with Deep Learning Analysis.
Raman spectroscopy has emerged as a powerful tool in medical, biochemical, and biological research with high specificity, sensitivity, and spatial and temporal resolution. Recent advanced Raman systems, such as portable Raman systems and fiber-optic probes, provide the potential for accurate in vivo discrimination between healthy and cancerous tissues. In our study, a portable Raman probe spectrometer was tested in immunosuppressed mice for the in vivo localization of colorectal cancer malignancies from normal tissue margins. The acquired Raman spectra were preprocessed, and principal component analysis (PCA) was performed to facilitate discrimination between malignant and normal tissues and to highlight their biochemical differences using loading plots. A transfer learning model based on a one-dimensional convolutional neural network (1D-CNN) was employed for the Raman spectra data to assess the classification accuracy of Raman spectra in live animals. The 1D-CNN model yielded an 89.9% accuracy and 91.4% precision in tissue classification. Our results contribute to the field of Raman spectroscopy in cancer diagnosis, highlighting its promising role within clinical applications.


Bioequivalence study of generic tablet formulations containing ethinylestradiol and chlormadinone acetate in healthy female volunteers.
The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and chlormadinone acetate (CAS 302-22-7) (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 h post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/ml (test) and 129.12 pg/ml (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/ml (test) and 6.6663 ng/m (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/ml x h (test) and 1380.49 pg/ml x h (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/ml x h (test) and 58.111 ng/ml x h (reference). The median of tmax of ethinylestradiol was 1.5 h for both test and reference and the median of tmax of chlormadinone acetate 1.0 h (test) and 1.5 h (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 h (test) and 15.41 h (reference) and of chlormadinone acetate 56.63 h (test) and 56.17 h (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90% confidence interval for the Cmax ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of Cmax of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and Cmax fall into the generally accepted range of 80%-125%.


20(s)-ginsenoside Rg3 promotes apoptosis in human ovarian cancer HO-8910 cells through PI3K/Akt and XIAP pathways.
Ovarian cancer is a serious tumor which represents a great threat to women's health. Recently, researchers had found that 20(s)-ginsenoside Rg3 could inhibit growth of several cancer cell lines; however, the mechanism is not fully understood so far. In the present study, we found that 20(s)-ginsenoside Rg3 reduced cell viability and induced apoptosis in a dose- and time-dependent manner in the human ovarian cancer cells HO-8910. The induction of apoptosis was accompanied by downregulation of phosphatidylinositol 3-kinase (PI3K)/Akt family proteins and inhibitor of apoptosis protein (IAP) family proteins. 20(s)-ginsenoside Rg3 treatment resulted in activation of caspase-3 and -9, which may partly explain the anti-cancer activity of 20(s)-ginsenoside Rg3. Taken together, our study for the first time suggests that 20(s)-ginsenoside Rg3 is able to enhance apoptosis of HO-8910 cells, at least in part, through downregulation of PI3K/Akt and IAP family proteins. Moreover, the triggering of caspase-3 and -9 activation mediated apoptotic induction. Our data indicate that 20(s)-ginsenoside Rg3 is an effective apoptosis-inducing natural compound in ovarian cancer cells and may have a role in future therapies for ovarian cancer.


Rethinking development interventions through the lens of decoloniality in sub-Saharan Africa: The case of global health.
There has been much talk about decolonizing global health lately. The movement, which has arisen in various communities around the world, suggests an interesting critique of the Western dominant model of representations. Building upon the 'decolonial thinking' movement from the perspective of Francophone African philosophers, we comment on its potential for inspiring the field of global healthinterventions. Using existing literature and personal reflections, we reflect on two widely known illustrations of global health interventions implemented in sub-Saharan Africa - distribution of contraceptives and dissemination of Ebola virus prevention and treatment devices - featuring different temporal backdrops. We show how these solutions have most often targeted the superficial dimensions of global health problems, sidestepping the structures and mental models that shape the actions and reactions of African populations. Lastly, we question the ways through which the decolonial approach might indeed offer a credible positioning for rethinking global health interventions.


Radial versus femoral approach comparison in percutaneous coronary intervention with intraaortic balloon pump support: the RADIAL PUMP UP registry.
The role of intraaortic balloon pump (IABP) during percutaneous coronary intervention (PCI) in high-risk acute patients remains debated. Device-related complications and the more complex patient management could explain such lack of clinical benefit. We aimed to assess the impact of transradial versus transfemoral access for PCI requiring IABP support on vascular complications and clinical outcome. We retrospectively analyzed 321 consecutive patients receiving IABP support during transfemoral (n = 209) or transradial (n = 112) PCI. Thirty-day net adverse clinical events (NACEs) (composite of postprocedural bleeding, cardiac death, myocardial infarction, target lesion revascularization, and stroke) were the primary end point, with access-related bleeding and hospital stay as secondary end points. Cardiogenic shock and hemodynamic instability were the most common indications for IABP support. Cumulative 30-day NACE rate was 50.2%, whereas an access site-related bleeding occurred in 14.3%. Patients undergoing transfemoral PCI had a higher unadjusted rate of NACEs when compared with the transradial group (57.4% vs 36.6%, P < .01), mainly due more access-related bleedings (18.7% vs 6.3%, P < .01). Such increased risk of NACEs was confirmed after propensity score adjustment (hazard ratio 0.57 [0.4-0.9], P = .007), whereas hospital stay appeared comparable in the 2 groups. In this observational registry, high-risk patients undergoing PCI and requiring IABP support appeared to have fewer NACEs if transradial access was used instead of transfemoral, mainly due to fewer access-related bleedings. Given the inherent limitations of this retrospective work, including the inability to adjust for unknown confounders, further controlled studies are warranted to confirm or refute these findings.


Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1.
To determine whether articular chondrocytes express growth factor genes delivered by adenoviral vectors and whether expression of these genes influences matrix synthesis in the presence and absence of interleukin-1 (IL-1). Monolayer cultures of rabbit articular chondrocytes were infected with recombinant adenovirus carrying genes encoding the following growth factors: insulin-like growth factor 1 (IGF-1), transforming growth factor beta1 (TGFbeta1), and bone morphogenetic protein 2 (BMP-2). As a control, cells were transduced with the lac Z gene. Cultures were also treated with each growth factor supplied as a protein. Levels of gene expression were noted, and the synthesis of proteoglycan, collagen, and noncollagenous proteins was measured by radiolabeling. Collagen was typed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The effects of growth factor gene transfer on proteoglycan synthesis in the presence of IL-1 were also measured. The expression of all transgenes was high following adenoviral transduction. Proteoglycan synthesis was stimulated approximately 8-fold by the BMP-2 gene and 2-3-fold by the IGF-1 gene. The effects of BMP-2 and IGF-1 genes were additive upon cotransduction. Synthesis of collagen and noncollagenous proteins, in contrast, was most strongly stimulated by the IGF-1 gene. In each case, collagen typing confirmed the synthesis of type II collagen. IL-1 suppressed proteoglycan synthesis by 50-60%. IGF-1 and TGFbeta genes restored proteoglycan synthesis to control levels in the presence of IL-1. The BMP-2 gene, in contrast, elevated proteoglycan synthesis beyond control levels in the presence of IL-1. Transfer of growth factor genes to articular chondrocytes can greatly increase matrix synthesis in vitro, even in the presence of the inflammatory cytokine IL-1. This result encourages the further development of gene therapy for the repair of damaged cartilage.


Rapid Self-Selecting and Clone-Free Integration of Transgenes into Engineered CRISPR Safe Harbor Locations in Caenorhabditis elegans.
Precision genome editing for model organisms has revolutionized functional analysis and validation of a wide variety of molecular systems. To date, the capacity to insert single-copy transgenes into the model nematode Caenorhabditis elegans has focused on utilizing either transposable elements or CRISPR-based safe harbor strategies. These methods require plate-level screening processes to avoid selecting heritable extrachromosomal arrays or rely on co-CRISPR markers to identify knock-in events. As a result, verification of transgene insertion requires anti-array selection screening methods and PCR genotyping. These approaches also rely on cloning plasmids for the addition of transgenes. Here, we present a novel safe harbor CRISPR-based integration strategy that utilizes engineered insertion locations containing a synthetic guide RNA target and a split-selection system to eliminate false positives from array formation, thereby providing integration-specific selection. This approach allows the experimenter to confirm an integration event has taken place without molecular validation or anti-array screening methods and is capable of producing integrated transgenic lines in as little as five days post-injection. To further increase the speed of generating transgenic lines, we also utilized the C. elegans native microhomology-based recombination, to assemble transgenes in-situ, removing the cloning step. We show that complete transgenes can be made and inserted into our split-selection safe harbor locations starting from PCR products, providing a clone-free and molecular-validation-free strategy for single-copy transgene integration. Overall, this combination of approaches provides an economical and rapid system for generating highly reproducible complex transgenics in C. elegans.


Physician recruitment: the role of the hospital information system.
Hospital information systems can support physician recruitment activities by helping identify the type of physician the institution needs, describe the type of medical practice a physician can expect, support the institution's strategic plan for the future, and demonstrate the institution's ability to assist a physician with his or her office billing and other administrative functions.


A Myoblast-Laden Collagen Bioink with Fully Aligned Au Nanowires for Muscle-Tissue Regeneration.
Contact guidance can promote cell alignment and is thus widely employed in tissue regeneration. In particular, skeletal muscle consists of long fibrous bundles of multinucleated myotubes formed by the fusion and differentiation of the satellite cells of myoblasts. Herein, a functional bioink and cell-printing process supplemented with an electric field are proposed for obtaining highly aligned myoblasts in a collagen-based bioink. To achieve the goal, we mixed Au nanowires (GNWs) with the collagen-based bioink to provide aligned topographical cues to the laden cells. Because the aligned GNWs could clearly provide topographical cues to the cells, we adjusted various processing parameters (flow rate, nozzle speed, and processing temperature) and applied an external electric field to optimally align the GNWs. By selecting an appropriate condition, the GNWs in the printed C2C12-laden structure were well aligned in the printing direction, and they eventually induced a high degree of myoblast alignment and efficient myotube formation. Through the several in vitro cellular activities and in vivo works revealing the myogenesis of the cell-laden structure, we conclude that the collagen/GNW-based cell-laden structure fabricated using the proposed method is a new prospective platform for the effective formation of muscle tissues.


Increasing fungal infections in the intensive care unit.
Yeasts and molds now rank among the most common pathogens in intensive care units. Whereas the incidence of Candida infections peaked in the late 1970s, aspergillosis is still increasing. Review of the pertinent English-language literature. Most factors promoting an invasive fungal infection are difficult to avoid because they are connected directly to treatment of the underlying disease. Antifungal treatment is often commenced on an empiric basis, whereas it might be preferable to adopt a strategy based on a diagnostic procedure able to demonstrate or exclude fungal disease. Polyenes have been the drugs of choice, but voriconazole is the new standard for aspergillosis. For invasive candidiasis, fluconazole is a more convenient option, with the new echinocandins or voriconazole as alternatives. The incidence of invasive fungal infection is increasing, but so too are the choices of agents for therapy. For reasons of efficacy and safety, therapy with an echinocandin or azole antifungal agent is supplanting the use of polyenes.


Exploring patients' reasons for participation in a medical education home visit program: a qualitative study in Malaysia.
Direct contact with patients for medical education is essential in healthcare professional training. Patients who were recruited for a medical education home visit program in Malaysia did so on a voluntary basis without remuneration. This paper aims to explore their reasons for participation in this program. An exploratory qualitative study was conducted on patients who had been visited during the 2012/2013 academic session. Purposive sampling was done to select adult participants from varying ethnicities and ages from the list of patients. In-depth interviews were conducted at the participants' homes and were audio recorded. The transcripts of these interviews were analyzed using thematic analysis. A total of nine in-depth interviews were conducted. Four main themes were identified from thematic analysis: 1) Perceived meaning of the visit; 2) Perceived benefits and risks; 3) Past healthcare experiences; 4) Availability for visits. The home visits meant different things to different participants, including a teaching-learning encounter, a social visit, a charitable deed or a healthcare check-up. The benefits and risks of accepting unknown students to their homes and sharing their health issues with them had been weighed prior to participation. Prior experience with healthcare services such as gratitude to healthcare providers or having a relative in the healthcare profession increased their receptivity for involvement. Lastly, enabling factors such as availability of time would determine their acceptance for home visits. Patients agree to participate in medical education activities on a voluntary basis for various reasons. Providing good healthcare service and sufficient preparation are crucial to increase patient receptivity for such activities.


Serious Games for Nutritional Education: Online Survey on Preferences, Motives, and Behaviors Among Young Adults at University.
Data on nutritional information and digital gameplay are limited among young adults in Germany. This survey aimed to gather data on nutritional information sources and digital games for nutritional education (preferences, motives, and behaviors) among young adults at both Munich universities in Germany. An online survey was developed by an multidisciplinary research group using EvaSys, an in-house survey software. The questionnaire (47 items) covered questions about baseline characteristics (eg, housing situation and weight), nutrition (eg, nutritional information sources), and digital (nutritional) gameplay (eg, preferences, motives, and behaviors). A feedback field was also provided. This publication is based on a selection of 20 questions (7 baseline characteristics, 2 nutrition, 11 gameplay). Young adults, primarily Munich university students aged from 18 to 24 years, were invited to participate by digital and nondigital communication channels between 2016 and 2017. Statistical analyses were performed using Excel 2013 (Microsoft Corp) and R version 3.1.3 (R Foundation for Statistical Computing). In total, 468 young adults (342/468, 73.1% women; 379/468, 81.0% university students) participated. Most of the participants (269/468, 57.5%) were aged 18 to 24 years with a BMI in the normal weight range (346/447, 77.4%). Mean body weight was 65.5 [SD 14.0] kg. Most participants reported getting nutritional information from the internet (372/467, 79.7%) and printed media (298/467, 63.8%), less than 1.0% (2/467, 0.4%) named digital games. Apps (100/461, 21.7%) and university/workplace (146/461, 31.7%) were the most desired sources for additional information about nutrition, while 10.0% (46/461, 10.0%) of participants stated wanting digital games. Almost two-thirds (293/468, 62.6%) of participants played digital games, while one-fifth (97/456, 21.3%) played digital games daily using smartphones or tablets. Finally, most respondents (343/468, 73.3%), mainly women, expressed interest in obtaining nutritional information during digital gameplay. However, significant gender differences were shown for nutritional acquisition behaviors and digital gameplay preferences, motives, and behaviors. Our survey population reported playing digital games (especially men) and wanting nutritional information during digital gameplay (especially women). Furthermore, university or workplace are named as preferred settings for nutritional information. Therefore, a digital game app might have the potential to be a tool for nutritional education among young adults within the university or workplace environment.


The receptor-like kinase SlSERK1 is required for Mi-1-mediated resistance to potato aphids in tomato.
The plant receptor-like kinase somatic embryogenesis receptor kinase 3 (SERK3)/brassinosteroid insensitive 1-associated kinase 1 (BAK1) is required for pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). Here we show that a distinct member of the SERK family, SERK1, is required for the full functioning of Mi-1, a nucleotide binding leucine-rich repeat (NB-LRR) resistance protein. Mi-1 confers resistance to Meloidogyne spp. (root-knot nematodes, RKNs) and three phloem-feeding insects, including Macrosiphum euphorbiae (potato aphid). SERK1 was identified in a tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS) screen in Nicotiana benthamiana. The screen was based on the suppression of a pest-independent hypersensitive response triggered by a constitutively active form of Mi-1, Mi-DS4. To assess the role of SERK1 in Mi-1-mediated resistance, Solanum lycopersicum (tomato) SlSERK genes were cloned. Three SlSERK members were identified with homologies to Arabidopsis AtSERK1 or AtSERK3/BAK1, and were named SlSERK1, SlSERK3A and SlSERK3B. SlSERK1 is ubiquitously expressed in tomato. Reducing SlSERK1 transcript levels in resistant plants, using gene-specific TRV-SERK1 VIGS, revealed a role for SlSERK1 in Mi-1-mediated resistance to potato aphids, but not to RKNs. In addition, Mi-1-dependent SlWRKY72 gene regulation was compromised in SlSERK1-silenced plants, placing SlSERK1 in the Mi-1 signaling pathway. Silencing SlSERK1 in a susceptible tomato background did not reduce the susceptibility to aphids, indicating that SlSERK1 is unlikely to be an essential virulence target. SlSERK1 is an active kinase, mainly localized at the plasma membrane. This work identifies a critical early component of Mi-1 signaling, and demonstrates a role for SlSERK1 in NB-LRR-mediated immunity.


Clinical and radiologic manifestations of sickle cell disease in the head and neck.
Sickle cell disease is a common inherited blood disorder that is characterized by the presence of sickle-shaped red blood cells. The clinical manifestations of sickle cell disease vary, but they may be attributed to three mechanisms: vaso-occlusion, chronic hemolytic anemia, and infection. The imaging appearances of central nervous system and musculoskeletal involvement by sickle cell disease have been well documented; however, involvement in the head and neck often is underappreciated, although it is not uncommon. In the head and neck, sickle cell disease can involve the inner ears, orbits, paranasal sinuses, bones, lymph nodes, and vessels. Manifestations of inner ear involvement include labyrinthine hemorrhage and labyrinthitis ossificans. In the orbits, they include lacrimal gland swelling, orbital wall infarction, and subperiosteal hemorrhage or fluid. In the paranasal sinuses, extramedullary hematopoiesis is seen. When bone is involved, infarction, osteomyelitis, bone marrow hyperplasia, and deposition of iron in bone marrow are seen in the maxillofacial bone and skull base. When lymph nodes are involved, lymphadenopathy is seen, and when blood vessels are involved, arterial stenosis and ectasia are seen. An understanding of the pathophysiology of sickle cell disease and knowledge of the various clinical and radiologic manifestations are crucial for prompt diagnosis and appropriate treatment.


Tick-transmitted infectious diseases in the United States.
The epidemiologic concept of tick-transmitted diseases has increased in importance with the recognition of the emerging infectious diseases, Lyme borreliosis, human monocytotropic and granulocytotropic ehrlichioses, and three different babesioses. Effective public health control of these diseases would depend upon critical knowledge of the vector biology of the ticks that transmit them. Rocky Mountain spotted fever and the human ehrlichioses are life-threatening yet treatable diseases. A major problem remains establishment of the diagnosis when treatment decisions are being made. Clinical manifestations, other than erythema migrans for Lyme borreliosis, do not provide strong diagnostic clues. Ehrlichiae or babesiae are often not detected in peripheral blood smears. Frequently there are no antibodies to these diverse agents at the time of presentation, and isolation does not yield sensitive and timely results. Polymerase chain reaction, still a research tool, promises the greatest sensitivity, specificity, and timeliness. Prevention by vaccines is not yet a reality, although OspA-based vaccines offer hope for the prevention of Lyme disease.


Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer.
Necitumumab (IMC-11F8), under development by ImClone Systems in collaboration with Bristol-Myers Squibb, is a fully human IgG1 mAb targeting the epidermal growth factor receptor (EGFR), for the potential intravenous treatment of cancer, in particular NSCLC. In vitro studies demonstrate that necitumumab inhibits downstream targets in the EGFR pathway (eg, MAPK), which are important for cellular proliferation, differentiation, invasion and metastasis. Furthermore, because necitumumab is an IgG1 construct, it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells. Preclinical studies indicated that the antitumor activity of necitumumab is either comparable with or superior to that of ImClone's chimeric anti-EGFR mAb cetuximab. In a phase I clinical trial in patients with advanced solid malignancies, necitumumab displayed nonlinear pharmacokinetic behavior. The toxicity profile of necitumumab is acceptable, with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date. Preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising. Success in the ongoing phase III clinical trials in patients with advanced NSCLC would lead to necitumumab becoming a valuable addition to future therapeutic strategies in oncology.


The MYBL1/TCFL5 transcription network: two collaborative factors with central role in male meiosis.
Male gametogenesis, spermatogenesis, is a stepwise developmental process to generate mature sperm. The most intricate process of spermatogenesis is meiosis during which two successive cell divisions ensue with dramatic cellular and molecular changes to produce haploid cells. After entry into meiosis, several forms of regulatory events control the orderly progression of meiosis and the timely entry into post-meiotic sperm differentiation. Among other mechanisms, changes to gene expression are controlled by key transcription factors. In this review, we will discuss the gene regulatory mechanisms underlying meiotic entry, meiotic progression, and post-meiotic differentiation with a particular emphasis on the MYBL1/TCFL5 regulatory architecture and how this architecture involves in various forms of transcription network motifs to regulate gene expression.


Infant feeding and feeding transitions during the first year of life.
Infancy is a time of rapid transition from a diet of virtually nothing but milk (either breast milk or infant formula) to a varied diet from nearly all food groups being consumed on a daily basis by most infants. Despite various recommendations about infant feeding, little is known about actual patterns of feeding among US infants. This article documents transitions in infant feeding patterns across the first year of life and determinants of key aspects of infant feeding. Using data from the Infant Feeding Practices Study II, we analyzed responses to a 7-day food-recall chart that was administered every month. The sample size declined from 2907 at birth to 1782 at 12 months of age. Although 83% of survey respondents initiated breastfeeding, the percentage who breastfed declined rapidly to 50% at 6 months and to 24% at 12 months. Many of the women who breastfed also fed their infants formula; 52% reported that their infants received formula while in the hospital. At 4 months, 40% of the infants had consumed infant cereal, 17% had consumed fruit or vegetable products, and <1% had consumed meat. Compared with infants who were not fed solid foods at 4 months, those who were fed solid foods were more likely to have discontinued breastfeeding at 6 months (70% vs 34%) and to have been fed fatty or sugary foods at 12 months (75% vs 62%). Supplementing breast milk with infant formula while infants were still in the hospital was very common. Despite recommendations that complementary foods not be introduced to infants aged 4 months or younger, almost half of the infants in this study had consumed solid foods by the age of 4 months. This early introduction of complementary foods was associated with unhealthful subsequent feeding behaviors.


Functional constraints of nuclear-mitochondrial DNA interactions in xenomitochondrial rodent cell lines.
The co-evolution of nuclear and mitochondrial genomes in vertebrates led to more than 100 specific interactions that are crucial for an optimized ATP generation. These interactions have been examined by introducing rat mtDNA into mouse cells devoid of mitochondrial DNA (mtDNA). When mtDNA-less cells derived from the common mouse (Mus musculus domesticus) were fused to cytoplasts prepared from Mus musculus, Mus spretus, or rat (Rattus norvegicus), a comparable number of respiring clones could be obtained. Mouse xenomitochondrial cybrids harboring rat mtDNA had a slower growth rate in medium containing galactose as the carbon source, suggesting a defect in oxidative phosphorylation. These clones respired approximately 50% less than the parental mouse cells or xenomitochondrial cybrids harboring Mus spretus mtDNA. The activities of respiratory complexes I and IV were approximately 50% lower, but mitochondrial protein synthesis was unaffected. The defects in complexes I and IV were associated with decreased steady-state levels of respective subunits suggesting problems in assembly. We also showed that the presence of 10% mouse mtDNA co-existing with rat mtDNA was sufficient to restore respiration to normal levels. Our results suggest that evolutionary distance alone is not a precise predictor of nuclear-mitochondrial interactions as previously suggested for primates.


Probabilistic phylogenetic inference with insertions and deletions.
A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth-death) evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new "concordance test" benchmark on real ribosomal RNA alignments, we show that the extended program dnamlepsilon improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm.


Medical Professionalism Across Cultures: A Literature Review.
This article was migrated. The article was marked as recommended. The review aims to identify the cultural perspectives of medical professionalism by identifying relevant literature from the Middle East, East/South Asia, and the Western world that discuss definitions. A literature search was conducted using the "Summon" search engine, and 200 articles sorted by relevancy were manually reviewed. Based on the surveys and documents gathered from each of the regions, the definitions seem to be fairly consistent in their recognition of characteristics important to the concept of medical professionalism. These include several characteristics, with some of the most common being personal character, respect for patient autonomy, responsibility, and social obligations; the main difference lies in emphasis with the West focusing on societal issues and patient rights, the Middle East focusing on morality and personal character, and East Asia focusing on respect, responsibility, and other duties. These differences are reviewed and the cultural sources are further expanded upon.


Why Young Women Who Use Opioids Are at Risk for Rape: The Impact of Social Vulnerabilities and Sexually Coercive Drug Using Contexts.
This study tests a theoretically informed model to understand why women who use opioids (WWUO) are at risk of rape while using drugs. Structured interviews were conducted with 168 WWUO. Three domains were hypothesized to increase risk: the sexually coercive context of drug use, women's social vulnerability, and drug use severity. Logistic regression examined the odds of being raped by domain. One-third of WWUO had been raped while using drugs. The sexually coercive context and social vulnerability domains significantly increased women's odds of being raped. Prevention efforts should target social and contextual factors.


The Carroll rating scale for depression. I. Development, reliability and validation.
The Carroll rating scales (CRS) was developed as a self rating instrument for depression, closely matching the information content and specific items of the Hamilton rating scales (HRS). The CRS was found to have acceptable face validity and reliability. The concurrent validity of the CRS was acceptable, based on comparisons with the HRS and the Beck Depression Inventory (BDI). The internal consistency of the CRS was very similar to that of the HRS. The CRS contained information about HRS scores beyond what could be predicted from BDI scores, but the BDI did not predict HRS scores beyond what could be predicted from CRS scores. The CRS and BDI scores were strongly correlated and both had access to a subjective dimension of depression that could not be predicted from HRS scores. The complementary uses of self ratings and observer ratings are evident from these results. The CRS may be a useful alternative to the BDI as a self rating scale, with the additional advantage of closer correspondence to the HRS.


The Additional Value of an E-Mail to Inform Healthcare Professionals of a Drug Safety Issue: A Randomized Controlled Trial in the Netherlands.
The usefulness and the impact of Direct Healthcare Professional Communications (DHPCs, or 'Dear Doctor letters') in changing the clinical behaviour of physicians have been debated. Changes in the current risk communication methods should preferably be based on the preferences of the healthcare professionals, to optimize the uptake of the message. The aim of this study was to assess whether safety issues are communicated more effectively with an additional e-mail sent by the Dutch Medicines Evaluation Board (MEB) than with the DHPC only. A randomized controlled trial was conducted amongst ophthalmologists and hospital pharmacists in the Netherlands, who were the target group of a DHPC that was issued for pegaptanib, a drug that is administered intra-ocularly in patients with macular degeneration. The intervention group (N = 110) received the pegaptanib DHPC, as well as the MEB e-mail. The control group (N = 105) received the traditional paper-based DHPC only. Two weeks later, the study population received an invitation to fill out an online questionnaire. Questions were asked about the respondents' knowledge and attitude regarding the pegaptanib issue, and any action they had consequently taken. Additional questions were asked about their satisfaction with the DHPC and the e-mail, and their preferred source of such information. Forty respondents (18.6%) completed the questionnaire. Eighty-one percent of the respondents in the intervention group (N = 21) and 47% of the control group (N = 19) correctly indicated that a serious increase in intra-ocular pressure could be caused by pegaptanib injections (Fishers' exact test, p = 0.046). Nine respondents in the intervention group versus none of the control group respondents indicated that they had taken action in response to the pegaptanib safety issue (Fishers' exact test, p = 0.01). The majority of both the intervention group and the control group confirmed that they would like to receive an MEB e-mail with safety information about drugs in the future (90 and 95 %, respectively). The results of this study indicate that an additional e-mail might strengthen the uptake of the safety information provided to healthcare professionals, who prefer to receive an e-mail from the MEB as a source of such information, as well as the DHPC. This study may serve as a starting point for new strategies to improve risk communication regarding safety issues associated with drugs and its impact on prescribing.


Oligodendroglial tumors.
Oligodendroglial tumors are relatively rare, comprising approximately 5% of all glial neoplasms. Oligodendroglial tumor patients have a better prognosis than those with astrocytic neoplasms, and patients with tumors that contain 1p/19q co-deletions or IDH-1 mutations appear to be particularly sensitive to treatment. In the past decade, scientists have made significant progress in the unraveling the molecular events that relate to the pathogenesis of these neoplasms. There is considerable excitement resulting from the recent reports from two large phase III randomized trials (European Organization for Research and Treatment of Cancer [EORTC] 26951 and Radiation Therapy Oncology Group [RTOG] 9402), which disclosed that patients with newly diagnosed 1p/19q co-deleted anaplastic oligodendroglial tumors have a 7+year increase in median overall survival following chemoradiation, as compared to radiation alone. This has stimulated a renewed interest in the development of new therapeutic strategies for treatment and potential cure of oligodendroglial tumors, based on an improved scientific understanding of the molecular events involved in the pathogenesis of these neoplasms. The goal of this document is to summarize the key translational developments and recent clinical therapeutic trial data, with a correlative perspective on current and future directions.