[Combined treatment of acute diffuse peritonitis].
Results of treatment in 199 patients were analysed. The patients were divided into 3 groups. In group 1 (80 patients) acute diffuse peritonitis was treated with conventional methods, in group 2 (62 patients) conventional treatment was supplemented by exchange plasmapheresis, in group 3 (57 patients) conventional treatment was used together with extracorporeal detoxication and elective relaparotomies. Plasmapheresis and elective relaparotomies resulted in increase of effectiveness of the treatment in acute diffuse peritonitis. The intervals between the elective relaparotomies and sessions of plasmapheresis depended on the stage and the course of peritonitis. Lethality rate in conventional method of treatment for acute diffuse peritonitis made up 39%, in plasmapheresis 29%, and in combined treatment--24.5%.


Chronic low back pain among tobacco farmers in southern Brazil.
Despite tobacco farming involving intensive manual labor, chronic low back pain (CLBP) prevalence and associated factors are unknown among this occupational group. This was a cross-sectional study conducted in southern Brazil. A random sample of tobacco farmers was interviewed. Socioeconomic and individual characteristics, occupational tasks, workloads, and comorbidities were investigated. Chronic low back pain prevalence was described in relation to independent variables, and associations were examined with Poisson regression. Chronic low back pain prevalence was 8·4%. Increasing age, rearing two or more species of livestock (PR 1·65), exposure to tasks that require heavy physical exertion (PR 2·00), working in awkward postures (PR 1·36), green tobacco sickness (GTS) (PR 1·63), pesticide poisoning (PR 2·37), and minor psychiatric disorders (PR 2·55) were associated with CLBP. This study found that CLBP is a relevant health problem among tobacco farmers and highlights understudied risk factors such as pesticide poisoning and GTS. Policies to minimize exposure to physiological and chemical workloads in tobacco planting to prevent CLBP are needed. Health professionals should be trained to diagnose and prevent acute low back pain episodes and thus prevent/minimize limitations and disabilities due to CLBP.


Automated determination of parameters describing power spectra of micrograph images in electron microscopy.
The current theory of image formation in electron microscopy has been semi-quantitatively successful in describing data. The theory involves parameters due to the transfer function of the microscope (defocus, spherical aberration constant, and amplitude constant ratio) as well as parameters used to describe the background and attenuation of the signal. We present empirical evidence that at least one of the features of this model has not been well characterized. Namely the spectrum of the noise background is not accurately described by a Gaussian and associated "B-factor;" this becomes apparent when one studies high-quality far-from focus data. In order to have both our analysis and conclusions free from any innate bias, we have approached the questions by developing an automated fitting algorithm. The most important features of this routine, not currently found in the literature, are (i). a process for determining the cutoff for those frequencies below which observations and the currently adopted model are not in accord, (ii). a method for determining the resolution at which no more signal is expected to exist, and (iii). a parameter-with units of spatial frequency-that characterizes which frequencies mainly contribute to the signal. Whereas no general relation is seen to exist between either of these two quantities and the defocus, a simple empirical relationship approximately relates all three.


Association of low plasma adiponectin with early diastolic dysfunction.
Diastolic dysfunction (DD) with preserved left ventricular (LV) ejection fraction (EF) has been linked to obesity. Adiponectin is a cytokine related to obesity and obesity-linked cardiovascular complications. The authors aimed to determine the independent association of DD with adiponectin. Fifty patients with impaired relaxation DD and a normal EF and age-matched normal controls were recruited. Plasma levels of total and high molecular weight (HMW) adiponectin were measured. Mid and low molecular weight (MMW+LMW) fractions of adiponectin were calculated by subtracting HMW fraction from total adiponectin. The DD group had significantly lower total (median, 4.4 vs 12.7 μg/mL; P=.001), HMW fraction (median, 1.3 vs 3.4 μg/mL; P=.02), and MMW+LMW fraction of adiponectin (median, 3.8 vs 7.2 μg/mL; P=.01). Body mass index (BMI) negatively correlated with total (r:-0.46, P=.003), HMW (r:-0.32, P=.038), and MMW+LMW (r:-0.40, P=.006) fractions of adiponectin. DD had an independent association with both BMI (P<.05) and total adiponectin (P<.001) in linear regression model using sex, BMI, blood pressure, and total adiponectin as covariates. DD was associated with BMI (P=.02), HMW fraction (P=.03), and MMW+LMW fraction (P=.004) in similar linear regression analyses. Adiponectin deficiency may be one explanation for the adiposity-related cardiac oxidation known to be involved in the pathogenesis of DD.


Pharmacology, distribution and development of muscarinic acetylcholine receptor subtypes in the optic tectum of Rana pipiens.
Visually evoked behaviors mediated by the frog optic tectum require cholinergic activity, but the receptor subtypes through which acetylcholine acts are not yet identified. Using quantitative autoradiography and scintillation spectrometry, we examined the binding of [3H]pirenzepine and [3H]AF-DX 384 in the laminated optic tectum of the frog. In mammalian systems, these substances bind excitatory (m1 and m3 subtypes) and inhibitory (m2 and m4 subtypes) muscarinic acetylcholine receptors, respectively. Pharmacological analyses, including the use of specific muscarinic toxins, confirmed the subtype selectivity of the radioligands in the frog brain. Binding sites for [3H]pirenzepine were distinct from those for [3H]AF-DX 384. In the adult tectum, [3H]pirenzepine demonstrated specific binding in tectal layers 5-9. [3H]Pirenzepine binding was also present in tadpoles as young as stage V, but all sampled stages of tadpole tectum had significantly less binding when compared to adults. Lesioning of the optic nerve had no effect on [3H]pirenzepine binding. Specific [3H]AF-DX 384 binding was found in all layers of the adult tectum. All sampled tadpole stages exhibited binding sites for [3H]AF-DX 384, but the densities of these sites were also significantly higher in adults than they were in developing stages. Short-term lesions of the optic nerve reduced [3H]AF-DX 384 binding in all tectal layers of the deafferented lobe when compared to the afferented one. Long-term lesions decreased [3H]AF-DX 384 sites in both lobes.These results indicate that multiple muscarinic acetylcholine receptor binding sites reside in the frog optic tectum at all stages of development, and their pharmacology resembles that of mammalian m1/m3, m2 and m4 subtypes. Our data indicate that few, if any, of these receptors are likely to be located on retinal ganglion cell terminals. Furthermore, the expression of inhibitory muscarinic subtypes seems to be regulated by different mechanisms than that for excitatory subtypes.


The Cincinnati initiative.
Nationwide, purchaser coalitions are forming to use their buying clout to reform the delivery of health care. In Cincinnati, a collaborative effort between purchasers and providers is producing profound changes in the local health care market. After the first year in operation, data show a significant overall decrease in length of stay (LOS), a return to single-digit inflation, and intriguing changes in provider practice patterns. These results have been achieved through voluntary hospital and physician practice pattern changes without additional contractual allowances, price controls, or utilization management imposed by the initiative. This article explores the development of the Cincinnati initiative, results to date, lessons learned, and future implications.


Sepsis and the Human Microbiome. Just Another Kind of Organ Failure? A Review.
Next-generation sequencing (NGS) has been further optimised during the last years and has given us new insights into the human microbiome. The 16S rDNA sequencing, especially, is a cheap, fast, and reliable method that can reveal significantly more microorganisms compared to culture-based diagnostics. It might be a useful method for patients suffering from severe sepsis and at risk of organ failure because early detection and differentiation between healthy and harmful microorganisms are essential for effective therapy. In particular, the gut and lung microbiome in critically ill patients have been probed by NGS. For this review, an iterative approach was used. Current data suggest that an altered microbiome with a decreased alpha-diversity compared to healthy individuals could negatively influence the individual patient's outcome. In the future, NGS may not only contribute to the diagnosis of complications. Patients at risk could also be identified before surgery or even during their stay in an intensive care unit. Unfortunately, there is still a lack of knowledge to make precise statements about what constitutes a healthy microbiome, which patients exactly have an increased perioperative risk, and what could be a possible therapy to strengthen the microbiome. This work is an iterative review that presents the current state of knowledge in this field.


Blunted endocrine and cardiovascular reactivity in young healthy women reporting a history of childhood adversity.
Chronic or prolonged stress exposure in childhood can alter structural and functional brain development, leading to mental and physical illness and alterations of psychobiological stress systems in adulthood. Recently, attenuation in stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and cardiovascular system have been related to the number of adverse childhood experiences (ACEs). We set out to investigate the association of ACE duration and age of ACE occurrence on stress reactivity. 104 women in the age range 18-25 years (mean=21.7) free of mental and physical illness underwent psychosocial stress testing with the Montreal Imaging Stress Task (MIST). Free saliva cortisol and heart rate were assessed repeatedly before and after the MIST. Number of ACEs was associated with attenuated cortisol and heart rate responses to stress in a dose-response relationship. Whereas overall duration of ACEs was significantly associated with an attenuated cortisol response, the specific age of first ACE occurrence did not contribute further to the dampened stress response. ACEs are associated with blunted endocrine and cardiovascular stress reactivity in young and healthy women. Adverse life events in childhood, particularly if they occur repeatedly and chronically, show a strong association with alterations in stress reactivity in adulthood, potentially predisposing for later mental or physical disorders.


Work function measurements during plasma exposition at conditions relevant in negative ion sources for the ITER neutral beam injection.
Cesium seeded sources for surface generated negative hydrogen ions are major components of neutral beam injection systems in future large-scale fusion experiments such as ITER. The stability and delivered current density depend highly on the work function during vacuum and plasma phases of the ion source. One of the most important quantities that affect the source performance is the work function. A modified photocurrent method was developed to measure the temporal behavior of the work function during and after cesium evaporation. The investigation of cesium exposed Mo and MoLa samples under ITER negative hydrogen ion based neutral beam injection relevant surface and plasma conditions showed the influence of impurities which result in a fast degradation when the plasma exposure or the cesium flux onto the sample is stopped. A minimum work function close to that of bulk cesium was obtained under the influence of the plasma exposition, while a significantly higher work function was observed under ITER-like vacuum conditions.


Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent.
The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.


The interplay between sex, time of day, fasting status, and their impact on cardiac mitochondrial structure, function, and dynamics.
Mitochondria morphology and function, and their quality control by mitophagy, are essential for heart function. We investigated whether these are influenced by time of the day (TOD), sex, and fed or fasting status, using transmission electron microscopy (EM), mitochondrial electron transport chain (ETC) activity, and mito-QC reporter mice. We observed peak mitochondrial number at ZT8 in the fed state, which was dependent on the intrinsic cardiac circadian clock, as hearts from cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit different TOD responses. In contrast to mitochondrial number, mitochondrial ETC activities do not fluctuate across TOD, but decrease immediately and significantly in response to fasting. Concurrent with the loss of ETC activities, ETC proteins were decreased with fasting, simultaneous with significant increases of mitophagy, mitochondrial antioxidant protein SOD2, and the fission protein DRP1. Fasting-induced mitophagy was lost in CBK mice, indicating a direct role of BMAL1 in regulating mitophagy. This is the first of its kind report to demonstrate the interactions between sex, fasting, and TOD on cardiac mitochondrial structure, function and mitophagy. These studies provide a foundation for future investigations of mitochondrial functional perturbation in aging and heart diseases.


Damage to the macula associated with LED-derived blue laser exposure: A case report.
Light emitting diodes laser is emerging as an important source of light replacing conventional lights. It is widely used for illumination in the bar where young people love to go. But not everyone knows about the light damage to the eye especially to the macula. In this article, we report the case of a macular damage induced by LED-derived blue laser in a bar, studied with optical coherence tomography (OCT) to evaluate the retinal lesion and multifocal electroretinography (mfERG) to evaluate functional damage. Four days after the photo injury to the right eye, the visual acuity was 0.5. Funduscopy revealed a round red lesion in the macula of the right eye. Fluorescein angiography (FA) revealed no leakage. OCT revealed a deficiency in the center of the fovea. MfERG revealed a reduction of the peak value in the right eye compared to the left eye. One month later, although the vision was 1.0 in the right eye, OCT revealed a hyporeflectivity of the ellipsoid zone. MfERG still showed a reduction of the peak value in the right eye compared to the left eye. We believe that general knowledge about laser injuries to the eye should be realized widely. We also think in cases of macular laser damage, the recovery of vision can not demonstrate the recovery of the function of photoreceptors.


A Cognitive Control-Inspired Approach to Object Tracking.
Under a tracking framework, the definition of the target state is the basic step for automatic understanding of dynamic scenes. More specifically, far object tracking raises challenges related to the potentially abrupt size changes of the targets as they approach the sensor. If not handled, size changes can introduce heavy issues in data association and position estimation. This is why adaptability and self-awareness of a tracking module are desirable features. The paradigm of cognitive dynamic systems (CDSs) can provide a framework under which a continuously learning cognitive module can be designed. In particular, CDS theory describes a basic vocabulary of components that can be used as the founding blocks of a module capable to learn behavioral rules from continuous active interactions with the environment. This quality is the fundamental to deal with dynamic situations. In this paper we propose a general CDS-based approach to tracking. We show that such a CDS-inspired design can lead to the self-adaptability of a Bayesian tracker in fusing heterogeneous object features, overcoming size change issues. The experimental results on infrared sequences show how the proposed framework is able to outperform other existing far object tracking methods.


[Do the adolescents have medical decision-making capacity? A sensitive issue for the doctor].
The physician who cares for adolescents should routinely assess the medical decision-making capacity of the minor. The physician must always ask whether the young person has the capacity of discernment, after having given the patient the necessary information, and before obtaining his consent. This analysis is helpful for the physician to determine who can make the decision, and to consider the limits of confidentiality. This paper reviews the Swiss law situation in terms of age limits, and provides information to guide the physician in the evaluation process with the use of practical questions and help of other professionals when in doubt.


Neuroeffector Ca2+ transients for the direct measurement of purine release and indirect measurement of cotransmitters in rodents.
Determining whether ATP and noradrenaline are released from the same vesicle at mature autonomic neuroeffector junctions is challenging because of the difficulty of simultaneously detecting the packeted release of these neurotransmitters. Contraction, overflow and electrophysiology experiments all show that both ATP and noradrenaline are released following field stimulation (although the ratio might vary) from autonomic nerves in tissues including the vas deferens, rat tail artery and mesenteric artery. The occurrence of purinergic neuroeffector Ca(2+) transients (NCTs) has been used to detect the packeted release of the neurotransmitter ATP acting on postjunctional P2X receptors to cause Ca(2+) influx. Neuroeffector Ca(2+) transients can also be used to detect the local effects of noradrenaline through its alpha(2)-adrenoceptor-mediated prejunctional autoinhibitory effects on nerve terminal Ca(2+) concentration and the probability of exocytosis (measured by counting NCTs). Evidence is presented that exocytosis from sympathetic varicosities does not occur in a manner independent of the history of that varicosity, but rather that the release of a packet of ATP transiently suppresses (or predicts the transient suppression of) subsequent release. This could arise by autoinhibition (by the prejunctional action of noradrenaline or purines) or due to a transient shortage of vesicles readily available for release. In summary, two high-resolution approaches are proposed to measure the intermittent release of packets of neurotransmitter: (1) local transient suppression of nerve terminal Ca(2+) transients; and (2) the local and transient inhibition of NCTs to infer local autoinhibition, hence transmitter release. Such approaches may allow the packeted corelease of ATP and noradrenaline to be investigated without the need to measure both neurotransmitters directly.


Neurolept analgesia in ambulatory (nasal) endoscopies.
Neurolept analgesia in ambulatory nasal endoscopies has been gaining widespread use recently. Scrupulous selection of patients and careful preoperative evaluation and premedication are essential. Excellent surgical block is a prerequisite to good neurolept analgesia. Versed (midazolam) is particularly suitable for outpatient surgery, since it provides superior operative condition to Valium (particularly less venoirritation) and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl (Sublimaze) or alfentanil, Versed is suitable for the provision of total neurolept analgesia. Careful intraoperative vigilance and monitoring, including pulse oximetry, cannot be overemphasized.


Association between the SLC6A4 gene and schizophrenia: an updated meta-analysis.
In order to explore the association between the SLC6A4 gene and the risk of schizophrenia, an updated meta-analysis was conducted using a total of 46 scientific articles. Through a literature search, papers studied included 35 articles on serotonin-transporter-linked polymorphic region (5-HTTLPR) with 8,752 cases and 10,610 controls, 17 articles on second intron variable number of tandem repeats with 7,284 cases and 8,544 controls, four studies on rs1042173 with 1,351 cases and 2,101 controls, and four studies on rs140700 with 1,770 cases and 2,386 controls. Pooled, subgroup, and sensitivity analyses were performed, and the results were visualized by forest and funnel plots. An association between 5-HTTLPR and the risk of schizophrenia was not found, except for an Indian subgroup analysis (Pz =0.014, OR =1.749, 95% CI =1.120-2.731). A 10 repeats/12 repeats (10R/12R) genotype was a protective factor against schizophrenia (Pz =0.020, OR =0.789, 95% CI =0.646-0.963), but a 12R/12R genotype was a risk factor for schizophrenia (Pz =0.004, OR =1.936, 95% CI =1.238-3.029) in the pooled analyses. In Caucasians, a GG genotype of rs1042173 may be a risk factor for schizophrenia (Pz =0.006, OR =1.299, 95% CI =1.079-1.565). No association was found between rs140700 and the risk for schizophrenia. Through meta-analysis, we were able to gain insight into previously reported associations between SLC6A4 polymorphism and schizophrenia.


Outcomes associated with court-ordered treatment over objection in an acute psychiatric hospital.
The postdischarge outcomes of court-ordered treatment of acute psychiatric inpatients have not been adequately investigated. We reviewed the medical records of all patients who refused medication for whom a court order was sought during a recent three-year period, and compared this group to control patients who agreed to treatment and a group of patients who transiently refused medication. The principal outcome measures were successful linkage after discharge, readmission within six months of discharge, and transfer to a state hospital. The study group was less likely to link to an aftercare provider, and more likely to be transferred to a state hospital, had poorer insight on admission, had a longer average stay, and was more likely to utilize mandatory outpatient treatment and long-acting injectable medications after discharge. Patients who require court-ordered medication over objection constitute a group that is high risk for nonadherence after discharge and being refractive to treatment.


NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1.
Phosphorylation regulates the function of ligand-gated ion channels such as the N-methyl d-aspartate (NMDA) receptor. Here we report a mechanism for modulation of the phosphorylation state and function of the NMDA receptor via an inhibitory scaffolding protein, RACK1. We found that RACK1 binds both the NR2B subunit of the NMDA receptor and the nonreceptor protein tyrosine kinase, Fyn. RACK1 inhibits Fyn phosphorylation of NR2B and decreases NMDA receptor-mediated currents in CA1 hippocampal slices. Peptides that disrupt the interactions between RACK1, NR2B, and Fyn induce phosphorylation and potentiate NMDA receptor-mediated currents. Therefore, RACK1 is a regulator of NMDA receptor function and may play a role in synaptic plasticity, addiction, learning, and memory.


HIV/AIDS-Associated Cryptococcosis in Portugal Spanning the Pre- to Post-HAART Era: A Retrospective Assessment at the Genotypic Level Based on URA5-RFLP.
Cryptococcosis caused by the fungus Cryptococcus neoformans is an opportunistic mycosis, infecting mainly immunodepressed individuals. Molecular epidemiology studies of cryptococcosis in Europe are limited. This paper presents a retrospective study of cryptococcosis in 105 cryptococcal isolates from two hospitals in Lisbon, Portugal, among HIV/AIDS patients, from 1991 to 2007. Among these patients, the number of cases of cryptococcosis increased from 5.1 to 6.9 cases per year from the pre- to post-highly active antiretroviral therapy (HAART) era. As expected, the median age of the patients increased, from 32 (mean: 33 ± 8) to 39 (mean: 41 ± 10) years, and the ratio of male to female patients remained high (7.7 and 7.6, respectively). Strain genotyping based on restriction fragment length polymorphism of the orotidine monophosphate pyrophosphorylase (URA5-RFLP) gene showed that, in general, the relative frequencies of the genotypes VNI-IV are similar to those from other European countries. These frequencies were, respectively, for the pre- and post-HAART periods: 41.7 and 43.5 % for VNI; 2.8 and 17.4 % for VNII; 38.9 and 30.4 % for VNIII; 16.7 and 7.2 % for VNIV and 0 and 1.4 % for VGII. Some apparent although statistically insignificant differences among these values were observed between both periods. The genotypic frequencies were not also statistically different according to the patients' gender or age range. Of note are the high proportion of VNIII isolates (common in Europe) and the high increase in the frequency of the VNII genotype in the post-HAART. Ultimately, these results may have implications in disease therapy, management and control.


Lowering Intraocular Pressure: A Potential Approach for Controlling High Myopia Progression.
High myopia is among the most common causes of vision impairment, and it is mainly characterized by abnormal elongation of the axial length, leading to pathologic changes in the ocular structures. Owing to the close relationship between high myopia and glaucoma, the association between intraocular pressure (IOP) and high myopia progression has garnered attention. However, whether lowering IOP can retard the progression of high myopia is unclear. On reviewing previous studies, we suggest that lowering IOP plays a role in progressive axial length elongation in high myopia, particularly in pathologic myopia, wherein the sclera is more remodeled. Based on the responses of the ocular layers, we further proposed the potential mechanisms. For the sclera, lowering the IOP could inhibit the activation of scleral fibroblasts and then reduce scleral remodeling, and a decrease in the scleral distending force would retard the ocular expansion like a balloon. For the choroid, lowering IOP results in an increase in choroidal blood perfusion, thereby reducing scleral hypoxia and slowing down scleral remodeling. The final effect of these pathways is slowing axial elongation and the development of scleral staphyloma. Further animal and clinical studies regarding high myopia with varied degree of IOP and the changes of choroid and sclera during IOP fluctuation in high myopia are needed to verify the role of IOP in the pathogenesis and progression of high myopia. It is hoped that this may lead to the development of a prospective treatment option to prevent and control high myopia progression.


Privacy-Preserving Deep Speaker Separation for Smartphone-Based Passive Speech Assessment.
Goal: Smartphones can be used to passively assess and monitor patients' speech impairments caused by ailments such as Parkinson's disease, Traumatic Brain Injury (TBI), Post-Traumatic Stress Disorder (PTSD) and neurodegenerative diseases such as Alzheimer's disease and dementia. However, passive audio recordings in natural settings often capture the speech of non-target speakers (cross-talk). Consequently, speaker separation, which identifies the target speakers' speech in audio recordings with two or more speakers' voices, is a crucial pre-processing step in such scenarios. Prior speech separation methods analyzed raw audio. However, in order to preserve speaker privacy, passively recorded smartphone audio and machine learning-based speech assessment are often performed on derived speech features such as Mel-Frequency Cepstral Coefficients (MFCCs). In this paper, we propose a novel Deep MFCC bAsed SpeaKer Separation (Deep-MASKS). Methods: Deep-MASKS uses an autoencoder to reconstruct MFCC components of an individual's speech from an i-vector, x-vector or d-vector representation of their speech learned during the enrollment period. Deep-MASKS utilizes a Deep Neural Network (DNN) for MFCC signal reconstructions, which yields a more accurate, higher-order function compared to prior work that utilized a mask. Unlike prior work that operates on utterances, Deep-MASKS operates on continuous audio recordings. Results: Deep-MASKS outperforms baselines, reducing the Mean Squared Error (MSE) of MFCC reconstruction by up to 44% and the number of additional bits required to represent clean speech entropy by 36%.


Frequency of Nonsuicidal Self-Injury in Adolescents: Differences in Suicide Attempts, Substance Use, and Disordered Eating.
The relationship between frequency of nonsuicidal selfinjury (NSSI) and suicide attempts, substance use, and disordered eating was assessed in a community sample of 4,839 adolescents, 922 of whom reported NSSI in the past year. It was expected that the engagement in risk behaviors would significantly increase as NSSI frequency increased. Participants completed the Youth Risk Behavior Survey (Centers for Disease Control and Prevention, 2009) and were subdivided into five NSSI frequency groups: none, 1 time, 2-3 times, 4-5 times, and 6 or more times. A one-way MANOVA found significant mean differences for all variables across NSSI frequency groups. The no NSSI group was significantly lower than all other groups on all variables. For suicide attempts, all frequency groups were significantly different from each other, with attempt frequency increasing with each increase in NSSI frequency. The six or more group reported significantly more substance use and disordered eating than all other groups. Overall, adolescents with more frequent NSSI represent a group at risk for concurrent unhealthy behaviors and suicide attempts.


The Middle to Later Stone Age transition at Panga ya Saidi, in the tropical coastal forest of eastern Africa.
The Middle to Later Stone Age transition is a critical period of human behavioral change that has been variously argued to pertain to the emergence of modern cognition, substantial population growth, and major dispersals of Homo sapiens within and beyond Africa. However, there is little consensus about when the transition occurred, the geographic patterning of its emergence, or even how it is manifested in the stone tool technology that is used to define it. Here, we examine a long sequence of lithic technological change at the cave site of Panga ya Saidi, Kenya, that spans the Middle and Later Stone Age and includes human occupations in each of the last five Marine Isotope Stages. In addition to the stone artifact technology, Panga ya Saidi preserves osseous and shell artifacts, enabling broader considerations of the covariation between different spheres of material culture. Several environmental proxies contextualize the artifactual record of human behavior at Panga ya Saidi. We compare technological change between the Middle and Later Stone Age with on-site paleoenvironmental manifestations of wider climatic fluctuations in the Late Pleistocene. The principal distinguishing feature of Middle from Later Stone Age technology at Panga ya Saidi is the preference for fine-grained stone, coupled with the creation of small flakes (miniaturization). Our review of the Middle to Later Stone Age transition elsewhere in eastern Africa and across the continent suggests that this broader distinction between the two periods is in fact widespread. We suggest that the Later Stone Age represents new short use-life and multicomponent ways of using stone tools, in which edge sharpness was prioritized over durability.


Occurrence of a fetal fibroblast phenotype in familial breast cancer.
We have previously shown that fetal and adult human skin fibroblasts display distinctive migratory phenotypes when cultured on 3-dimensional collagen gels in vitro. In the present study, we have used this information to assess the migratory behavior of fibroblasts obtained from patients with either benign or malignant breast disease, and correlated this with the presence of a family history of breast cancer. We have observed that fibroblasts from 17/34 patients with no previous family history of breast cancer displayed fetal-type behavior in our assay system; in contrast, fibroblasts from 15/16 patients with a positive family history of breast cancer behaved abnormally. This apparently increased probability of expressing a fetal-type migratory phenotype in the patients with a family history is statistically significant (p less than 0.008). Skin fibroblasts obtained from 2 healthy and unaffected first-degree relatives (one male and one female) of patients with a family history of breast cancer also exhibited a fetal-type migratory phenotype.


SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis.
The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.


Integration of the reflex pharyngeal swallow into rhythmic oral activity in a neurologically intact pig model.
Mammalian swallowing involves the coordinated and sequential activity of many oropharyngeal muscles. Using synchronous electromyography (EMG) and videofluorography, we recorded the pattern of EMG activity for 12 muscles during swallowing in neurologically intact suckling pigs. We tested the hypothesis that this EMG pattern corresponded to the established pattern of activity for the isolated, reflexive pharyngeal swallow of the decerebrate infant pig. The EMG activity associated with the normal swallow of the intact animal had two components: a staggered pattern of single EMG bursts that were prominent in the stylohyoid, thyrohyoid, cricothyroid, and omohyoid muscles and double bursts of activity in some muscles, including geniohyoid and genioglossus, with the same underlying periodicity as suckling. Most of the staggered activity pattern, a linear sequence of progressively delayed activities in different muscles, was not statistically different from that previously found in the reflexive pharyngeal swallow of the decerebrate. However, not all components of the linear sequence of the reflexive swallow were inserted unchanged into the intact swallow. Some components appeared to be delayed or advanced, bringing them into phase with the underlying rhythmic activity. The difference between swallows of intact and of decerebrate animals was not solely due to the presence of rhythmic activity in the former. The timing of some EMG activities in intact animals also differed from the same activities in the few decerebrates that exhibited rhythmic tongue and jaw activity. These results suggest cerebral function influences the EMG pattern of the pharyngeal swallow, which has traditionally been considered a purely reflex pattern.


[Changes in the levels of atrial natriuretic factor, aldosterone, cyclic nucleotides and beta 2-microglobulin in patients with myocardial infarction after ultrasonic therapy].
A total of 43 patients were examined: 21 patients with large myocardial infarction (MI) and 22 donors. In MI patients without signs of left ventricular failure, the level of atrial natriuretic factor was higher than that in the controls, which resulted in inhibition of aldosterone production; whereas in those with the signs, it was slightly lower than that in healthy individuals. All the patients with MI were found to have elevated blood plasma levels of cyclic nucleotides and beta 2-microglobulin. Ultrasound application to the heart was demonstrated to normalize secretion of atrial natriuretic factor, to increase plasma cyclic nucleotide levels and to produce no effects on beta 2-microglobulin quantities.


Genome assembly with in vitro proximity ligation data and whole-genome triplication in lettuce.
Lettuce (Lactuca sativa) is a major crop and a member of the large, highly successful Compositae family of flowering plants. Here we present a reference assembly for the species and family. This was generated using whole-genome shotgun Illumina reads plus in vitro proximity ligation data to create large superscaffolds; it was validated genetically and superscaffolds were oriented in genetic bins ordered along nine chromosomal pseudomolecules. We identify several genomic features that may have contributed to the success of the family, including genes encoding Cycloidea-like transcription factors, kinases, enzymes involved in rubber biosynthesis and disease resistance proteins that are expanded in the genome. We characterize 21 novel microRNAs, one of which may trigger phasiRNAs from numerous kinase transcripts. We provide evidence for a whole-genome triplication event specific but basal to the Compositae. We detect 26% of the genome in triplicated regions containing 30% of all genes that are enriched for regulatory sequences and depleted for genes involved in defence.


Diagnostic issues in the clinical management of pericarditis.
To review the current major diagnostic issues on the diagnosis of acute and recurrent pericarditis. To review the current available evidence, we performed a through search of several evidence-based sources of information, including Cochrane Database of Systematic Reviews, Clinical Evidence, Evidence-based guidelines from National Guidelines Clearinghouse and a comprehensive Medline search with the MeSH terms 'pericarditis', 'etiology' and 'diagnosis'. The diagnosis of pericarditis is based on clinical criteria including symptoms, presence of specific physical findings (rubs), electrocardiographical changes and pericardial effusion. Although the aetiology may be varied, most cases are idiopathic or viral, even after an extensive diagnostic evaluation. In such cases, the course is often benign following anti-inflammatory treatment, and management would be not affected by a more precise diagnostic evaluation. A triage of pericarditis can be safely performed on the basis of the clinical and echocardiographical presentation. Specific diagnostic tests are not warranted if no specific aetiologies are suspected on the basis of the epidemiological background, history and presentation. High-risk features associated with specific aetiologies or complications include: fever > 38 degrees C, subacute onset, large pericardial effusion, cardiac tamponade, lack of response to aspirin or a NSAID. A targeted diagnostic evaluation is warranted in acute and recurrent pericarditis, with a specific aetiological search to rule out tuberculous, purulent or neoplastic pericarditis, as well as pericarditis related to a systemic disease, in selected patients according to the epidemiological background, presentation and clinical suspicion.


Comparing Charlson and Elixhauser comorbidity indices with different weightings to predict in-hospital mortality: an analysis of national inpatient data.
Understanding how comorbidity measures contribute to patient mortality is essential both to describe patient health status and to adjust for risks and potential confounding. The Charlson and Elixhauser comorbidity indices are well-established for risk adjustment and mortality prediction. Still, a different set of comorbidity weights might improve the prediction of in-hospital mortality. The present study, therefore, aimed to derive a set of new Swiss Elixhauser comorbidity weightings, to validate and compare them against those of the Charlson and Elixhauser-based van Walraven weights in an adult in-patient population-based cohort of general hospitals. Retrospective analysis was conducted with routine data of 102 Swiss general hospitals (2012-2017) for 6.09 million inpatient cases. To derive the Swiss weightings for the Elixhauser comorbidity index, we randomly halved the inpatient data and validated the results of part 1 alongside the established weighting systems in part 2, to predict in-hospital mortality. Charlson and van Walraven weights were applied to Charlson and Elixhauser comorbidity indices. Derivation and validation of weightings were conducted with generalized additive models adjusted for age, gender and hospital types. Overall, the Elixhauser indices, c-statistic with Swiss weights (0.867, 95% CI, 0.865-0.868) and van Walraven's weights (0.863, 95% CI, 0.862-0.864) had substantial advantage over Charlson's weights (0.850, 95% CI, 0.849-0.851) and in the derivation and validation groups. The net reclassification improvement of new Swiss weights improved the predictive performance by 1.6% on the Elixhauser-van Walraven and 4.9% on the Charlson weights. All weightings confirmed previous results with the national dataset. The new Swiss weightings model improved slightly the prediction of in-hospital mortality in Swiss hospitals. The newly derive weights support patient population-based analysis of in-hospital mortality and seek country or specific cohort-based weightings.


Defensive endosymbionts: a cryptic trophic level in community ecology.
Maternally transmitted endosymbionts are widespread among insects, but how they are maintained within host populations is largely unknown. Recent discoveries show that some endosymbionts protect their hosts from pathogens or parasites. Spiroplasma, an endosymbiont of Drosophila neotestacea, protects female hosts from the sterilizing effects of parasitism by the nematode Howardula aoronymphium. Here, we show that Spiroplasma spreads rapidly within experimental populations of D. neotestacea subject to Howardula parasitism, but is neither strongly favored nor selected against in the absence of Howardula. In a reciprocal experiment, Howardula declined steadily to extinction in populations of Spiroplasma-infected flies, whereas in populations of uninfected flies, the prevalence of Howardula parasitism increased to c. 100%. Thus, Spiroplasma and Howardula exhibit effectively consumer-resource trophic dynamics. The recent spread of Spiroplasma in natural populations of D. neotestacea coincides with a decline in the prevalence of Howardula parasitism in the wild.


Emerging therapy-related kidney disease.
Many new therapies have emerged within the last 5 to 10 years to treat a variety of conditions. Several of these have direct or indirect renal toxicities that may go undiagnosed without careful attention of the pathologist to a patient's clinical history, particularly the addition of new medications or treatments. To discuss patterns of renal injury resulting from medications or therapeutic regimens that have been introduced within the last 10 years. Recognition of these patterns may allow the pathologist to alert the attending clinician to a possible drug-induced renal injury and prevent further deterioration of renal function and possible chronic kidney disease. A review of recent literature and unpublished observations of case-derived material. A number of newer therapies have emerged as agents of renal toxicity, producing a variety of pathologic changes in the kidney. The outcome can be acute or chronic glomerular, tubular, interstitial, and/or vascular injury. Some drugs will result in irreversible changes and end-stage renal disease, whereas many of the alterations can be reversed with removal of the offending agent, avoiding potential long-term kidney injury.


Thermal transport along the dislocation line in silicon carbide.
We elucidate thermal conductivity along the screw dislocation line, which represents a transport direction inaccessible to classical theories. By using equilibrium molecular dynamics simulations, we uncover a Burgers vector dependent thermal conductivity reduction in silicon carbide. The effect is uncorrelated with the classical modeling and originates in the highly deformed core region, which represents a significant source of anharmonic phonon-phonon scattering. High strain reduces the phonon relaxation time, especially in the longitudinal acoustic branches, and creates an effective internal thermal resistance around the dislocation axis. Our results have implications for designing materials useful for high-temperature electronics and thermoelectric applications.


Substoichiometric determination of zinc with potassium ethyl xanthate.
A rapid radiochemical method has been designed for the determination of microgram quantities of zinc, based on the substoichiometric isotope dilution, using potassium ethyl xanthate as the extraction reagent. pH 5.5 in acetate buffers and chloroform as the extractant were found to be suitable for quantitative substoichiometric extraction. The influence of the diverse ions on the extraction was studied. The zinc contents of a medicinal preparation and biological samples were determined by the present method.


Rotational dynamics of spin-labelled muscle proteins.
Electron paramagnetic resonance (EPR) spectroscopy on spin-labelled proteins was used to investigate the role of rotational motions in the two key ATPase systems of muscle: (a) the force-generating interaction of myosin and actin and (b) the calcium pump of sarcoplasmic reticulum (SR). The spin labels in these studies were rigidly fixed to the protein framework, so there were none of the nanosecond motions detectable by conventional EPR techniques. Thus conventional EPR was useful only in the study of static orientation in oriented systems (parallel muscle fibres or membrane bilayers), while saturation transfer EPR was required to detect protein motions in the microsecond range. Spin labels attached to myosin 'heads' were used to test the proposal that these heads form force-generating cross-bridges to actin that rotate when driven by the ATPase cycle. These probes are highly oriented and strongly immobilized when heads are bound to actin, but undergo microsecond rotations when the heads are detached from actin. During contraction, the majority of heads are mobile and disoriented, indicating detachment, while the remainder appear to be attached with the same orientation as in the absence of ATP. Thus the probed part of the myosin head does not appear to rotate during force generation. Saturation transfer EPR was used to monitor the microsecond rotational motions of the Ca2+-ATPase in SR membranes, while conventional EPR was used to monitor lipid hydrocarbon rotations in the microsecond time range. Changes in lipid fluidity and protein mobility, induced by changes in lipid/protein ratio, lipid composition, [Ca2+] and protein cross-linking, correlate well with changes in enzymic activity, suggesting the importance of molecular motions for Ca2+ transport.


The nucleotide sequence of the tnpA gene of Tn21.
The nucleotide sequence of the tnpA gene of Tn21 is presented. The transposase encoded by this gene is exactly the same length (988 amino acids) as the Tn501 transposase (4), and shows 72% homology overall with this protein, with greater homology towards the C-terminus. The sequence of the transposase is discussed in the context of the evolution of Class II transposable elements and of the characteristics of the enzyme's action.


Spinal instability in ankylosing spondylitis.
Unstable spinal lesions in patients with ankylosing spondylitis are common and have a high incidence of associated neurological deficit. The evolution and presentation of these lesions is unclear and the management strategies can be confusing. We present retrospective analysis of the cases of ankylosing spondylitis developing spinal instability either due to spondylodiscitis or fractures for mechanisms of injury, presentations, management strategies and outcome. In a retrospective analysis of 16 cases of ankylosing spondylitis, treated surgically for unstable spinal lesions over a period of 12 years (1995-2007); 87.5% (n=14) patients had low energy (no obvious/trivial) trauma while 12.5% (n=2) patients sustained high energy trauma. The most common presentation was pain associated with neurological deficit. The surgical indications included neurological deficit, chronic pain due to instability and progressive deformity. All patients were treated surgically with anterior surgery in 18.8% (n=3) patients, posterior in 56.2% (n=9) patients and combined approach in 25% (n=4) patients. Instrumented fusion was carried out in 87.5% (n=14) patients. Average surgical duration was 3.84 (Range 2-7.5) hours, blood loss 765.6 (+/- 472.5) ml and follow-up 54.5 (Range 18-54) months. The patients were evaluated for pain score, Frankel neurological grading, deformity progression and radiological fusion. One patient died of medical complications a week following surgery. Intra-operative adverse events like dural tears and inadequate deformity correction occurred in 18.7% (n=3) patients (Cases 6, 7 and 8) which could be managed conservatively. There was a significant improvement in the Visual analogue score for pain from a pre-surgical median of 8 to post-surgical median of 2 (P=0.001), while the neurological status improved in 90% (n=9) patients among those with preoperative neurological deficit who could be followed-up (n =10). Frankel grading improved from C to E in 31.25% (n=5) patients, D to E in 12.5% (n=2) and B to D in 12.5% (n=2), while it remained unchanged in the remaining - E in 31.25% (n=5), B in 6.25% (n=1) and D in 6.25% (n=1). Fusion occurred in 11 (68.7%) patients, while 12.5% (n=2) had pseudoarthrosis and 12.5% (n=2) patients had evidence of inadequate fusion. 68.7% (n=11) patients regained their pre-injury functional status, with no spine related complaints and 25% (n=4) patients had complaints like chronic back pain and deformity progression. In one patient (6.2%) who died of medical complications a week following surgery, the neurological function remained unchanged (Frankel grade D). Persistent back pain attributed to inadequate fusion/ pseudoarthrosis could be managed conservatively in 12.5% (n=2) patients. Progression of deformity and pain secondary to pseudoarthrosis, requiring revision surgery was noted in one patient (6.2%). One patient (6.2%) had no neurological recovery following the surgery and continued to have nonfunctional neurological status. In ankylosing spondylitis, the diagnosis of unstable spinal lesions needs high index of suspicion and extensive radiological evaluation Surgery is indicated if neurological deficit, two/three column injury, significant pain and progressive deformity are present. Long segment instrumentation and fusion is ideal.


Femoral osteolysis around the unrevised stem during isolated acetabular revision.
Many surgeons treat progressive femoral osteolysis in association with a well-fixed stem with bone grafting but in uncontained proximal defects the graft could get into the joint, raising a question regarding whether the osteolysis can be treated by simple débridement without bone grafting. We investigated whether the curetted proximal osteolysis around an unrevised femoral component progressed in size and whether this lesion would have a deleterious effect on fixation of the femoral component in patients with isolated acetabular revision. We prospectively followed 21 patients (24 hips) who underwent acetabular revision and curetting of femoral osteolysis. The minimum followup was 3 years (mean, 4.3 years; range, 3-7.4 years). By the latest followup, no hips had major progression of the osteolytic defect through the followup period and none had any new osteolytic lesions. All hips were judged stable and to have well-fixed acetabular cups and femoral stems. Provided a femoral component is bone ingrown with osseointegration sufficient to provide long-term stability, the osteolytic defect is in the proximal aspect of the femur, and the defect is uncontained, simple curettage may preserve femoral implant stability and may prevent progression of osteolysis to another Gruen zone for at least 3 to 7 years. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


The risk of developing Crohn's disease after an appendectomy: a meta-analysis.
Studies exploring the association between appendectomy and Crohn's disease (CD) have reported conflicting findings. We conducted a systematic review of the literature and a meta-analysis to assess the risk of CD following an appendectomy and determine the effect of time between appendectomy and CD diagnosis. MEDLINE was used to identify observational studies evaluating the association between appendectomy and CD. Authors were contacted when data were insufficient. Relative risks (RR) with 95% confidence intervals (CI) were calculated using a random effects model. Studies that analyzed their data by the interval between the appendectomy and the diagnosis of CD were assessed separately. The Woolf chi(2) statistic was used to test for homogeneity. Egger's test was used to evaluate publication bias. The summary RR estimate for CD following an appendectomy was significantly elevated (RR 1.61, 95% CI 1.28-2.02), though heterogeneity was observed (P < 0.0001). The risk was elevated within the first year following the operation (RR 6.69, 95% CI 5.42-8.25). The risk of CD was also significantly increased 1-4 yr following an appendectomy (RR 1.99, 95% CI 1.66- 2.38); however, after 5 yr or more, the risk fell to baseline levels (RR 1.08, 95% CI 0.99-1.18). Publication bias was not detected (P = 0.2). The meta-analysis demonstrated a significant risk of CD following an appendectomy, though heterogeneity was observed between the studies. The elevated risk early after an appendectomy, which diminishes thereafter, likely reflects diagnostic problems in patients with incipient CD.


Basic description and some notes on the evolution of seven sympatric morphs of Dolly Varden Salvelinus malma from the Lake Kronotskoe Basin.
The study examines the basic morphological and ecological features of Dolly Varden from Lake Kronotskoe (Russia, Kamchatka). Seven valid morphs different in head proportions, feeding, timing, and place of spawning have been determined in this ecosystem. The basic morphometric characteristics clearly separate Lake Kronotskoe morphs from each other, as well as from its potential ancestor (Dolly Varden). According to CVA analysis, the most notable morphological characteristics determining the mouth position are the length of a lower jaw and rostrum. Furthermore, five of seven morphs inhabit different depth zones of the lake and feed on different food resources. Our data suggest that reproductive isolation may be maintained by temporal/spatial isolation for two morphs with lacustrine spawning, and by spatial isolation only for the rest of the morphs with riverine spawning. The sympatric diversity of the Lake Kronotskoe charrs is exceptionally wide, and there are no other examples for seven sympatric morphs of genus Salvelinus to coexist within a single ecosystem. This study puts forward a three-step hypothetical model of charr divergence in Lake Kronotskoe as a potential ground for future studies.


ORMDL3 gene is associated with asthma in three ethnically diverse populations.
Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association. A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American. We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects. We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol. Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.


Tumor-associated macrophages in multiple myeloma: advances in biology and therapy.
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Tumor-associated macrophages (TAMs) are a major population of cells in the tumor site. Rather than contributing to the immune response against tumor cells, TAMs in many cancers are found to exhibit protumor properties including supporting chemoresistance, tumor proliferation and survival, angiogenesis, immunosuppression, and metastasis. Targeting TAM represents a novel strategy for cancer immunotherapy, which has potential to indirectly stimulate cytotoxic T cell activation and recruitment, and synergize with checkpoint inhibitors and chemotherapies. In this review, we will provide an updated and comprehensive overview into the current knowledge on the roles of TAMs in MM, as well as the therapeutic targets that are being explored as macrophage-targeted immunotherapy, which may hold key to future therapeutics against MM.


Heterogeneity in diabetes mellitus--update, 1978. Evidence for further genetic heterogeneity within juvenile-onset insulin-dependent diabetes mellitus.
The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studied that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent immunologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.


Donor leukocyte transfusions for leukemic relapse.
Treatment of recurrent leukemia after bone marrow transplantation with the transfusion of lymphocytes from the marrow donor has been successful in a majority of patients with chronic myelogenous leukemia and a minority of patients with acute myeloid leukemia and myelodysplastic syndrome. It has been disappointing in patients with acute lymphoblastic leukemia and in advanced stages of chronic myelogenous leukemia. In chronic-phase chronic myelogenous leukemia remissions were of good quality and the actuarial relapse rate was less than 20% at 3 years. In acute leukemias remissions were less durable. Graft-versus-host disease and marrow aplasia were the major complications of this form of treatment. In patients with marrow aplasia hematopoiesis could be restored by infusion of donor marrow without further conditioning treatment. Preceding or concomitant treatment with interferon alpha is not essential for a response, but the exact role of interferon alpha remains to be determined in a randomized study. Similarly, the best time for treatment remains to be defined. Treatment of cytogenetic and molecular recurrence of chronic myelogenous leukemia is most effective in preventing marrow aplasia, but a few patients may be treated unnecessarily, for some cytogenetic recurrences may remit spontaneously. The mechanism of the graft-versus-leukemia reaction is still not clear. Effector cells and target antigens remain to be defined. Observations are compatible with a graft-versus-host reaction directed against minor histocompatibility antigens presented at the cell surface of hematopoietic cells, but reactions against leukemia-specific antigens are possible. Future studies will focus on differences of reactions against possible leukemia-specific antigens and histocompatibility antigens on hematopoietic cells and cells of other organs.


Reasons for poor uptake of TB preventive therapy in South Africa.
South Africa has one the highest TB and HIV burdens globally. TB preventive therapy (TPT) reduces the risk of TB disease and TB-related mortality in adults and children living with HIV and is indicated for use in TB-exposed HIV-negative individuals and children. TPT implementation in South Africa remains suboptimal. We conducted a pragmatic review of TPT implementation using multiple data sources, including informant interviews (n = 134), semi-structured observations (n = 93) and TB patient folder reviews in 31 health facilities purposively selected across three high TB burden provinces. We used case descriptive analysis and thematic coding to identify barriers and facilitators to TPT implementation. TPT programme implementation was suboptimal, with inadequate monitoring even in health districts with well-functioning TB services. Health workers reported scepticism about TPT effectiveness, deprioritised TPT in practice and expressed divergent opinions about the cadres of staff responsible for implementation. Service- and facility-level barriers included ineffective contact tracing, resource shortages, lack of standardised reporting mechanisms and insufficient patient education on TPT. Patient-level barriers included socio-economic factors. Improving TPT implementation will require radically simplified and more feasible systems and training for all cadres of health workers. Partnership with communities to stimulate demand driven service uptake can potentially facilitate implementation.


Curcumin-loaded oil body emulsions prepared by an ultrasonic and pH-driven method: Fundamental properties, stability, and digestion characteristics.
In this study, oil bodies (OBs) loaded with curcumin (Cur) were successfully prepared via an ultrasonic and pH-driven method. Ultrasonic treatment significantly improved the encapsulation efficiency (EE) and loading capacity (LC) of Cur, producing OB particles with small size, uniform distribution, and high ζ-potential absolute values. When the ultrasonic power was 200 W, the EE, LC, and ζ-potential absolute value were the greatest (88.27 %, 0.044 %, and -25.71 mV, respectively), and the OBs possessed the highest yellowness, representing the best treatment result. The confocal laser scanning microscopy (CLSM) and cryo-scanning electron microscopy (cryo-SEM) results was also intuitionally shown that. Moreover, circular dichroism (CD) proved that ultrasonic treatment could unfold the surface protein structure, further enhancing the stability. Therefore, the cream index (CI), peroxide value (POV), and thiobarbituric acid reactive substances (TBARS) were the lowest when the ultrasonic power was 200 W. In this case, the Cur loaded in OBs was well protected against hostile conditions, evidenced by the highest Cur retention rate and the lowest degradation rate constant. Finally, the in vitro gastrointestinal digestion simulation results showed that the ultrasonic treatment effectively increased the release of FFA, bioaccessibility, and stability of Cur, especially when the ultrasonic power was 200 W. This research offers a new OB-based delivery system to stabilize, deliver, and protect Cur for food processing.


Torus mandibularis affects the severity and position-dependent sleep apnoea in non-obese patients.
Various anatomical structures of upper airway and physical differences are known to be risk factors for obstructive sleep apnoea (OSA). Torus mandibularis is a structure that can appear on the inside of the mandible. Therefore, it is possible for tori to influence airway volume by occupying the space for tongue and cause sleep apnoea. The purpose of this study is to investigate the effect of torus mandibularis on the severity of OSA as one of the craniofacial risk factors. Retrospective case-control study. University-based tertiary medical centre. Adult patients over 19-years-old who visited outpatient clinics with complaints of sleep-disordered breathing symptoms between January 2010 and December 2017 were investigated. The presence of torus mandibularis in oral cavity was confirmed by physical examination or CT image. We analysed demographic findings including age, sex, medical history, previous operation history, physical findings of upper airway and result of polysomnography. To evaluate the effect of torus mandibularis on OSA, polysomnography data of the two groups according to presence or absence of torus mandibularis were compared and analysed. Two-hundred and thirty-two OSA patients with BMI <25 were divided into two groups, according to either the presence or absence of torus mandibularis. We analysed 138 patients of control group and 94 of torus mandibularis group. Apnoea-hypopnoea index (AHI) was 18.8 ± 14.9 in control group and 25.1 ± 18.4 in torus mandibularis group (P = 0.006). Respiratory disturbance index (RDI) was 23.1 ± 14.7 in control group and 27.9 ± 18.4 in torus mandibularis group (P = 0.035). Supine AHI showed 26.6 ± 20.3 in control group and 32.5 ± 22.6 in torus mandibularis group (P = 0.039). Patients with torus mandibularis had a trend of increase in proportion according to the severity of sleep apnoea, such as AHI (P = 0.007) or RDI (P = 0.034). We newly found that the presence of torus mandibularis affects not only severity of OSA and also position-dependent OSA. These results support the necessity of torus mandibularis evaluation in OSA patients, and further study is also required to investigate its consequence in the surgical outcome.


Increasing our understanding of reactivity to pedometers in adults.
To investigate the presence of reactivity, if any, to wearing sealed and unsealed pedometers, with and without step count recording. On the first visit to the laboratory, 63 participants (41 females and 22 males; age = 23.6 +/- 9.6 yr, body mass index = 22.7 +/- 3.0 kg x m(-2)), blinded to the study aim, were provided with a sealed pedometer (New Lifestyles NL-1000) and informed that it was a "body posture monitor" (covert monitoring). Participants wore the pedometer throughout waking hours for 1 wk. On return to the laboratory, stored step counts were downloaded, and participants were informed that the device was a pedometer. Participants wore the pedometer under three more conditions-sealed, unsealed, and unsealed plus logging daily steps in an activity diary-each having a duration of 1 wk. The order of participation in each condition (sealed/unsealed/diary) was balanced across participants. Mean daily step counts recorded during the four conditions were compared using a repeated-measures ANOVA. There was a significant overall effect of condition (P < 0.001; covert monitoring = 8362 +/- 2600 steps per day; sealed condition = 8832 +/- 2845 steps per day; unsealed condition = 9176 +/- 3299 steps per day; diary condition = 9635 +/- 2709 steps per day), with post hoc analyses revealing that mean step counts were significantly higher in the diary condition than those reported during both the covert and sealed conditions (both P < 0.003). No significant gender effects were observed (P = 0.33). The greatest increase in step counts occurred in the diary condition, suggesting that reactivity to pedometers is greatest when participants are requested to wear an unsealed pedometer and record their step counts. This has validity implications for short-term pedometer studies investigating habitual free-living activity that require participants to provide a daily log of their step counts.


Unexpected recovery from a vegetative state or misdiagnosis? Lesson learned from a case report.
Growing research is focusing on the identification of markers predicting recovery and demonstrating covert awareness in patients with chronic disorders of consciousness (DOC). Herein, we describe the case of a woman who emerged from unresponsive wakefulness syndrome (UWS) after four years, in whom an experimental protocol assessing brain connectivity predicted her awareness recovery, indicating a functional locked-in syndrome (FLIS) diagnosis. A 68-year-old woman was admitted to our institute in 2012 in a UWS secondary to a severe brain hemorrhage, with a Coma Recovery Scale-Revised score of five. Her clinical conditions were stable for about two years, despite the intensive neurorehabilitation treatment. During hospitalization, she underwent a neurophysiological protocol demonstrating an extensive nociceptive processing within the pain matrix. After 3 years, our subject emerged from UWS, and then from minimally conscious state, being able to communicate properly. Approaches investigating brain connectivity may be useful in DOC diagnosis and prognosis, highlighting residual brain networks subtending covert awareness. Hence, our case supports the necessity of taking into account FLIS diagnosis in DOC differential diagnosis and implementing paraclinical follow-up to intercept cases of possible, late recovery of consciousness, thus optimizing the most appropriate management and rehabilitative setting.


Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension.
Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.


Computational analysis of gene regulation in animal sleep deprivation.
Sleep is an animal behavior shared by a wide range of species, suggesting that it must serve fundamental functions. However, the functions and molecular mechanisms underlying sleep are largely unknown. Through a meta-analysis of all available short-term sleep deprivation (SD) microarray data in mouse brain, we identified 91 key mouse SD-affected genes and two RBM3 isoforms showing opposite changes of expression during SD. Although most of the key SD-affected genes showed consistent changes of expression during SD across brain subregions despite their heterogeneous basal expression levels, we also identified the genes whose SD responses strongly depend upon the brain subregion. A gene regulatory network was also constructed for these genes showing that cAMP-responsive element (CRE) is one of the key cis-regulatory elements controlling SD-affected genes. We observed that SD during an animal's normal sleeping time could significantly disturb the circadian oscillation of clock genes. Surprisingly, synaptogenesis markers were significantly underexpressed in SD mice, differing from the previous findings in rat and fly. Comparing SD microarray data in mouse, rat, sparrow, and fly, we identified Egr and Nr4a gene families as conserved SD-affected genes, thus shedding new light on the origin of sleep in animals.


Absence of the septum pellucidum. Overlapping clinical syndromes.
A patient with absence of the septum pellucidum, optic hypoplasia, congenital nystagmus, hemiatrophy, and seizures fulfilled clinical and radiological criteria for diagnosis of both septo-optic dysplasia and the syndrome of absent septum pellucidum with porencephalies. The anatomical and clinical similarities between these two syndromes suggest a common embryological basis. Their simultaneous presence in this case further supports this explanation. Clinically mild forms of both septo-optic dysplasia and the syndrome of absent septum pellucidum with porencephalies are now detected with the aid of computed tomographic scanning in patients with unexplained hemiatrophy, congenital nystagmus, seizures, and short stature.


Network Profile: Improving Response to Malaria in the Amazon through Identification of Inter-Community Networks and Human Mobility in Border Regions of Ecuador, Peru, and Brazil.
Understanding human mobility's role on malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission. A community-level network survey. We collect data on community connectivity along three river systems in the Amazon basin: the Pastaza river corridor spanning the Ecuador-Peru border; and the Amazon and Javari river corridors spanning the Brazil-Peru border. We interviewed key informants in Brazil, Ecuador, and Peru, including from indigenous communities: Shuar, Achuar, Shiwiar, Kichwa, Ticuna, and Yagua. Key informants are at least 18 years of age and are considered community leaders. Weekly, community-level malaria incidence during the study period. We measure community connectivity across the study area using a respondent driven sampling design. Forty-five communities were initially selected: 10 in Brazil, 10 in Ecuador, and 25 in Peru. Participants were recruited in each initial node and administered a survey to obtain data on each community's mobility patterns. Survey responses were ranked and the 2-3 most connected communities were then selected and surveyed. This process was repeated for a third round of data collection. Community network matrices will be linked with eadch country's malaria surveillance system to test the effects of mobility on disease risk. To date, 586 key informants were surveyed from 126 communities along the Pastaza river corridor. Data collection along the Amazon and Javari river corridors is ongoing. Initial results indicate that network sampling is a superior method to delineate migration flows between communities. Our study provides measures of mobility and connectivity in rural settings where traditional approaches are insufficient, and will allow us to understand mobility's effect on malaria transmission. Strength: Community networks are unmeasured in rural areas of the Amazon, but have been shown to capture human mobility in other regions of the world.Strength: Our design captures social, economic, and human wellbeing connectivity and migration in key indigenous communities along the Peru-Ecuador border as well as in the most important confluence for the Amazon River located in the Brazil-Peru-Colombia tri-country intersection.Strength: Our design quantifies cross-border human mobility between communities, as well as the magnitude, timing, duration, and reason for mobility, which provides actionable information for malaria control and elimination programs in the regionLimitation: Migration decisions occur at individual and household levels that are coupled with environmental change and seasonality, meaning that our measures of community mobility may not be stable over time and we may be subject to ecological fallacy by inferring individual risk from community networks.Limitation: Our study relies on passive surveillance to test the community network/human mobility link with malaria. However, there exist cases that are asymptomatic, unreported (i.e., treated with traditional medicines), or that occur in our community network but are reported elsewhere. The extent of these cases can significantly increase uncertainty. This work was supported by the US National Institutes of Health (R01 AI51056; William K. Pan, PI) and by a grant from the Duke Climate and Health Initiative (William Pan, PI). PRC-U was supported by CONCYTEC through the PROCIENCIA program under the call entitled "Science, Technology and Innovation Thesis and Internships" according to the contract PE501081617-2022. AGL, CSC, EJA and PRC-U were sponsored by Emerge, the Emerging Diseases Epidemiology Research Training grant D43 TW007393 awarded by the Fogarty International Center of the US National Institutes of Health. We declare no conflicts.


Retinoic acid deficiency alters second heart field formation.
Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2(-/-) knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2(-/-) embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2(-/-) embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2(-/-) mutant heart, in a gene dosage-dependent manner.


An unusual case of congenital double coronary arteriovenous fistula.
A double coronary arteriovenous fistula (CAVF) was observed in a ten-year-old girl. A large, tortuous, and elongated right coronary artery, communicating with the right ventricle, was detected by two-dimensional echocardiography and confirmed at angiography. To our knowledge, no echocardiographic recognition of the origin and termination of a CAVF has been reported previously. Moreover, another fistula, connecting the left anterior descending coronary artery with the main pulmonary artery was also detected by selective left coronary arteriography. The anatomy of double CAVF was confirmed on surgery. A right CAVF draining into the right ventricle and a left CAVF draining into the main pulmonary artery seemed to be a very unusual combination.


Who are the people in your neighborhood? A descriptive analysis of individuals on public sex offender registries.
Despite growing focus on registration and notification systems as central elements of national sex offender management practice, there has been remarkably little systematic analysis of the content of these registries and the diversity of individuals contained within them. Specifically, little research attention has been paid to examining the heterogeneity of the population of registered sex offenders - a circumstance that may obscure important distinctions within the population and, in turn, may undermine the ostensible purpose of SORN to prevent sexual victimization. Addressing this significant gap in our current knowledge, this article sets forth a national profile of the registered sex offender (RSO) population, drawn from an analysis of data on 445,127 RSOs obtained from the public registries of 49 states, Washington, DC, Puerto Rico and Guam. In contrast with the homogenized perception about registered sex offenders that permeates much public discourse, the analysis illuminates the wide diversity of registrants across a range of demographic, offense-related, registry status, and risk-oriented variables. Policy and practice implications concerning risk, prevention, and the public safety utility of sex offender registries are discussed.


Oxytocin increases eye-gaze towards novel social and non-social stimuli.
Research on oxytocin (OT) has revealed a substantial involvement of this neuropeptide in social cognition processes and attachment behavior. The rationale of the present project was to decipher the differential role of OT in basic social cognition processes towards non-erotic attachment stimuli vs. reproduction-related stimuli in human subjects. In a randomized double-blind repeated-measures cross-over design, N = 82 participants were investigated twice and received either intranasal OT or placebo at the first assessment followed by placebo or OT at second assessment. Participants were presented with standardized pictures of parent-child dyads, romantic couples engaging in non-erotic or explicit sexual activities, and non-social pictures while we assessed pupil dilation and eye focus on specific pre-defined areas of interest. Multilevel analyses suggest that during the initial presentation, OT increased pupil dilation towards all categories of stimuli and led the eye focus towards the eyes and body regions, followed by a strong decrease in pupil dilation and fixations at the second session. These carry-over effects indicate that hormonal treatment at an initial contact to social stimuli can determine how these stimuli are processed later. These results might have implications for OT as a treatment in interventions with repeated exposure to social material.


Immunization. Around the world in 80 shots.
Physicians counseling patients who are planning major travels should make sure that baseline immunizations (diphtheria-tetanus-pertussis, polio, measles, rubella) and any necessary boosters are current. In addition, several other immunizations may be warranted (yellow fever, typhoid, and cholera), depending on destination(s) and itinerary, and prophylaxis for malaria may be advisable. As worldwide requirements for immunization do change, the physician should verify current requirements before planning an immunization schedule for a particular patient.


Report on 153 sequential three-incision robotic-assisted pulmonary resections by a single surgeon: technical details and learning curve.
There are several techniques for robotic-assisted pulmonary resection, depending on the number and position of ports and utility incisions. We developed a technique for three-incision robotic-assisted pulmonary resection, and here we reported our initial results. Three-incision pulmonary resection with the da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA, USA) was attempted in 153 patients. Robotic instruments were used for individual dissection of the hilar structures through two thoracoscopic ports and a 3-cm utility incision without rib spreading. Data on patient characteristics and perioperative results were prospectively collected. Between December 2016 and December 2018, a single surgeon performed three-incision robotic-assisted pulmonary resection on 153 consecutive patients in the Thoracic Surgery Department of the Second Xiangya Hospital. There was no emergent conversion to thoracotomy. Median operative time was 146.84 minutes (range, 40-320 minutes), and the median estimated blood loss was 62.70 mL (range, 5-200 mL). The mean postoperative days before chest tubes were removed was 3.91 (range, 2-18), and the mean postoperative days before patients were discharged was 5.34 (range, 2-20). The median number of lymph node stations dissected was 5 (range, 1-9). The mean number of nodes resected was 12 (range, 1-35), and postoperative complications were observed in 12 patients (7.84%). Three-incision robotic-assisted pulmonary resection is practicable, safe, and ideal for novices experienced in video-assisted thoracic surgery (VATS) surgery. It also appears to be oncologically acceptable for lung cancer; however, more studies on a large population are necessary to confirm these conclusions.


Race as a factor for intensification of diabetes medications.
The purpose of this study was to investigate if patients of nonwhite race are less likely to receive insulin therapy for treatment of poorly controlled diabetes than patients of white race. A retrospective review was performed of patients with an A1C >10%. The primary objective was to determine any difference in the initiation of insulin between white and nonwhite patients. Secondary outcomes measured the impact of clinic type and provider specialty on the initiation of insulin therapy. Exclusion criteria included those patients with type 1 diabetes mellitus, those who were previously receiving insulin, and those without an outpatient clinic visit within 14 days of an A1C >10%. A total of 277 patients were included. Of these patients, 132 (47.7%) were white, followed by 95 (34.2%) black non-Hispanic patients and 30 (10.8%) Hispanic/Latino patients. No difference was found in receipt of insulin therapy for nonwhite patients as compared to white patients (12.5 vs 21.4, P = .117). Neither clinic type nor provider specialty impacted initiation of insulin therapy. No changes to medication regimen were made at 35% of clinic visits. Failure to intensify diabetic medications was common in this outpatient setting. There were no disparities in the receipt of insulin therapy between white and nonwhite patients.


Diagnostic procedures of the skin. Part one: Wood's light, KOH slide, Gram's stain, and cultures.
The diagnosis of skin lesions involves the same priniciples and methodology required in other medical problems. Visual recognition alone and "shotgun" therapy is not a satisfactory clinical approach. A disciplined and careful examination of lesions, establishment of a differential diagnosis, and selection of appropriate procedures are frequently necessary for cutaneous diseases. The indications, limitations, interpretation, and techniques of diagnostic procedures must be well understoood to obtain reliable information. Not all tinea capitis will reveal fluorescence with Wood's light examination, but the Wood's light may be particularly helpful in the diagnosis of tinea versicolor, erythrasma, porphyria, and tuberous sclerosis. Bacterial growth on cultures taken from the skin does not necessarily mean infection. Because the eczematous skin teems with bacteria, there must be a careful interpretation of the cultures results within the context of the clinical situation. This paper is the first in a two-part series dealing with selected cutaneous procedures which are useful to the family physician in everyday practice.


Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 deletion syndrome.
22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia. Brain responses to auditory stimuli have been studied extensively in schizophrenia and described as potential biomarkers of vulnerability to psychosis. We sought to understand whether these responses might aid in differentiating individuals with 22q11.2DS as a function of psychotic symptoms, and ultimately serve as signals of risk for schizophrenia. A duration oddball paradigm and high-density electrophysiology were used to test auditory processing in 26 individuals with 22q11.2DS (13-35 years old, 17 females) with varying degrees of psychotic symptomatology and in 26 age- and sex-matched neurotypical controls (NT). Presentation rate varied across three levels, to examine the effect of increasing demands on memory and the integrity of sensory adaptation. We tested whether N1 and mismatch negativity (MMN), typically reduced in schizophrenia, related to clinical/cognitive measures, and how they were affected by presentation rate. N1 adaptation effects interacted with psychotic symptomatology: Compared to an NT group, individuals with 22q11.2DS but no psychotic symptomatology presented larger adaptation effects, whereas those with psychotic symptomatology presented smaller effects. In contrast, individuals with 22q11.2DS showed increased effects of presentation rate on MMN amplitude, regardless of the presence of symptoms. While IQ and working memory were lower in the 22q11.2DS group, these measures did not correlate with the electrophysiological data. These findings suggest the presence of two distinct mechanisms: One intrinsic to 22q11.2DS resulting in increased N1 and MMN responses; another related to psychosis leading to a decreased N1 response.


mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection.
T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.


Myofacial pain dysfunction: a clinical examination procedure.
Myofacial pain dysfunction (MPD), a commonly occurring illness, presents with a variety of clinical appearances and patient symptoms which mimic many other illnesses. The family physician and medical specialist are often first consulted by patients suffering from the pain and/or limited functions associated with MPD. Although the definitive diagnosis and therapy is usually provided by a dental specialist, the attending physician is often required to make the initial clinical diagnosis of MPD and then select proper referrals and consultations. Physicians with an understanding of the cause and clinical picture of MPD can, by obtaining a comprehensive history and performing a concise clinical examination, make a diagnosis of MPD. A description of the nature of the illness and a clinical examination procedure are presented.


Community-based plan for treating human immunodeficiency virus-infected individuals sponsored by local medical societies and an acquired immunodeficiency syndrome service organization.
Individuals infected with human immunodeficiency virus frequently experience difficulty finding medical care from private physicians. Fear of occupational exposure, prejudice, lack of knowledge, and financial loss have all been cited as reasons for the reluctance of primary care physicians to accept patients with acquired immunodeficiency syndrome into their practices. To meet the medical needs of all patients infected with human immunodeficiency virus, this Virginia community adopted a voluntary rotational referral plan to provide primary care for all such individuals. The program required the cooperation of a voluntary pool of internists and family practitioners and an acquired immunodeficiency syndrome service organization with a volunteer physician advisor to coordinate referrals of unassigned patients. No physician received more than three referrals per year. During the 2 years of operation, 118 referrals were made to 30 physicians. Regular educational seminars were provided with medical updates and consultation support was provided. This locally based program appears to be meeting the acquired immunodeficiency syndrome challenge in this community and may have applicability to other communities as well.