Can subjective pain be inferred from objective physiological data? Evidence from patients with sickle cell disease.
Patients with sickle cell disease (SCD) experience lifelong struggles with both chronic and acute pain, often requiring medical interventMaion. Pain can be managed with medications, but dosages must balance the goal of pain mitigation against the risks of tolerance, addiction and other adverse effects. Setting appropriate dosages requires knowledge of a patient's subjective pain, but collecting pain reports from patients can be difficult for clinicians and disruptive for patients, and is only possible when patients are awake and communicative. Here we investigate methods for estimating SCD patients' pain levels indirectly using vital signs that are routinely collected and documented in medical records. Using machine learning, we develop both sequential and non-sequential probabilistic models that can be used to infer pain levels or changes in pain from sequences of these physiological measures. We demonstrate that these models outperform null models and that objective physiological data can be used to inform estimates for subjective pain.


Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials.
Stimulated 5-hydroxytryptamine-3 (5-HT(3)) receptors promote intestinal motility, secretion, and sensation, effects that are related to the known pathophysiology of irritable bowel syndrome (IBS). A previous meta-analysis of 6 randomized controlled trials of the 5-HT(3)-receptor antagonist alosetron found that this agent was associated with global improvement in symptoms, pain, and discomfort in patients with IBS. This was a meta-analysis of randomized, placebo-controlled trials that evaluated the efficacy and tolerability of alosetron for the management of IBS. It updated and expanded on the previous meta-analysis. PubMed, EMBASE, SCOPUS, Web of Science, and the cochrane central Register of controlled Trials were searched from 1966 through September 2007 for placebo-controlled trials that examined the efficacy and tolerability of alosetron in the management of IBS. The search terms were alosetron, 5-HT, irritable bowel, functional bowel diseases, and irritable colon. No language restriction was applied. The data were analyzed in terms of 2 main outcomes: global improvement in IBS symptoms and adequate relief of IBS pain and discomfort. Eight multicenter, randomized, placebo-controlled, 12-week clinical trials met the criteria for inclusion in the meta-analysis. The studies included 4,170 patients with IBS (80% female) who were randomized to receive either alosetron or placebo. All patients met the Rome criteria for IBS, and all subtypes of IBS were represented. Most patients had diarrhea-predominant IBS; only 2.6% of patients had constipation-predominant IBS. In the 3 trials included in the analysis of global improvement in symptoms, alosetron was significantly more effective than placebo (relative risk [RR] = 1.60; 95% CI, 1.44-1.76; P <0.001). In the 6 trials included in the analysis of adequate relief of IBS pain and discomfort, there was also a significant difference in favor of alosetron (RR = 1.31; 95% CI, 1.20-1.43; P < 0.001). Analysis of adequate relief of IBS pain and discomfort by sex also indicated significant differences between alosetron and placebo in both sexes (female: RR = 1.34 [95% cI, 1.21-1.48]; male: RR = 1.23 [95% CI, 1.02-1.47]). The analysis of tolerability, which was based on data from 7 studies, found a significant difference between alosetron and placebo (RR = 1.19; 95% cI, 1.07-1.31; P<0.001). The only adverse events that occurred with a significantly higher incidence in those treated with alosetron compared with placebo were constipation in 8 trials (RR = 4.35; 95% CI, 3.01-6.26; P < 0.001) and abdominal pain and discomfort in 5 trials (RR = 1.96; 95% CI, 1.46-2.64; P < 0.001). In the alosetron group, there were 4 cases of ischemic colitis (0.16%) and 2 cases of serious complications of constipation (0.08%); neither of these was reported in the placebo group. Alosetron was not associated with any deaths. Alosetron was effective in these men and women with IBS. constipation was the most frequently reported adverse event associated with alosetron therapy. Ischemic colitis and serious complications of constipation were reported in a small number of patients treated with alosetron.


Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures.
Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract).


An analysis of deep vein thrombosis in 1277 consecutive neurosurgical patients undergoing routine weekly ultrasonography.
Patients requiring neurosurgical intervention are known to be at increased risk for deep vein thrombosis (DVT) and attendant morbidity and mortality. Pulmonary embolism (PE) is the most catastrophic sequela of DVT and is the direct cause of death in 16% of all in-hospital mortalities. Protocols for DVT screening and early detection, as well as treatment paradigms to prevent PE in the acute postoperative period, are needed in neurosurgery. The authors analyzed the effectiveness of weekly lower-extremity venous duplex ultrasonography (LEVDU) in patients requiring surgical intervention for cranial or spinal pathology for detection of DVT and prevention of PE. Data obtained in 1277 consecutive patients admitted to a major tertiary care center requiring neurosurgical intervention were retrospectively reviewed. All patients underwent admission (within 1 week of neurosurgical intervention) LEVDU as well as weekly LEVDU surveillance if the initial study was normal. Additional LEVDU was ordered in any patient in whom DVT was suspected on daily clinical physical examination or in patients in whom chest CT angiography confirmed a pulmonary embolus. An electronic database was created and statistical analyses performed. The overall incidence of acute DVT was 2.8% (36 patients). Of these cases of DVT, a statistically significant greater number (86%) were discovered on admission (within 1-7 days after admission) screening LEVDU (p < 0.05), whereas fewer were documented 8-14 days after admission (2.8%) or after 14 days (11.2%) postadmission. Additionally, for acute DVT detection in the present population, there were no underlying statistically significant risk factors regarding baseline physical examination, age, ambulatory status, or type of surgery. The overall incidence of acute symptomatic PE was 0.3% and the mortality rate was 0%. Performed within 1 week of admission in patients who will undergo neurosurgical intervention, LEVDU is effective in screening for acute DVT and initiating treatment to prevent PE, thereby decreasing the overall mortality rate. Routine LEVDU beyond this time point may not be needed to detect DVT and prevent PE unless a change in the patient's physical examination status is detected.


Evolution of reproductive modes in sharks and rays.
The ecological and life history drivers of the diversification of reproductive modes in early vertebrates are not fully understood. Sharks, rays and chimaeras (group Chondrichthyes) have an unusually diverse variety of reproductive modes and are thus an ideal group to test the factors driving the evolution of reproductive complexity. Here, using 960 species representing all major Chondrichthyes taxa, we reconstruct the evolution of their reproduction modes and investigate the ecological and life history predictors of reproduction. We show that the ancestral Chondrichthyes state was egg-laying and find multiple independent transitions between egg-laying and live-bearing via an intermediate state of yolk-only live-bearing. Using phylogenetically informed analysis, we also show that live-bearing species have larger body size and larger offspring than egg-laying species. In addition, live-bearing species are distributed over shallow to intermediate depths, while egg-layers are typically found in deeper waters. This suggests that live-bearing is more closely associated with pelagic, rather than demersal habitats. Taken together, using a basal vertebrate group as a model, we demonstrat how reproductive mode co-evolves with environmental conditions and life-history traits.


EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review.
The spectrum of mesenchymal tumors associated with rearrangements of the EWSR1 gene has been growing in recent years due to progress in molecular detection techniques. Originally identified as the gene involved in the pathogenesis of Ewing sarcoma, the EWSR1 gene is now known to be rearranged in diverse clinical and histopathological entities. The NFATC2 gene is one of the many translocation partners of EWSR1 in gene fusions in a morphologically typical, albeit rare, subgroup of mesenchymal tumors. Little is known about the clinical characteristics of tumors containing NFATC2 gene rearrangements since most of the few reports published describe molecular rather than clinical aspects. In the current study, we report three patients with tumors carrying the EWSR1-NFATC2 gene translocation, including one rare primary tumor of soft tissues. Another patient with a benign-appearing bone tumor with a unique FUS-NFATC2 gene translocation is described. In various mesenchymal tumors (e.g., myxoid/round cell liposarcoma, low-grade fibromyxoid sarcoma, or angiomatoid fibrous histiocytoma), the FUS gene, as a member of the TET family, may be alternatively rearranged instead of the EWSR1 gene without any noticeable influence on the microscopical appearance or clinical outcome. This fact seems not to apply to mesenchymal tumors with the involvement of the NFATC2 gene because both in our experience and according to the extensive literature review, they have different properties on the morphological and molecular level. Both ESWSR1-NFATC2 and FUS-NFATC2 fusion-carrying tumors do not show microscopical or clinical features of Ewing sarcoma.


Femtosecond Laser Combined with Double-Flange Polypropylene Suture Capsular Tension Ring Suspension for the Treatment of Subluxation of Lens in Marfan Syndrome.
To evaluate the use of femtosecond laser combined with double-flange polypropylene suture capsular tension ring (CTR) suspension to treat subluxation of lens in Marfan syndrome. The objective is to provide safer and more effective surgical procedures for patients. Setting. Eye Hospital, Aier Eye Hospital of Wuhan University, Wuhan, China. In this retrospective study, we observed sixteen patients (16 eyes) with Marfan syndrome who had undergone this operation. Femtosecond laser incision was performed on the anterior capsule with the lens as the center. The suspending CTR was clipped to anterior capsule to support it, which was secured to the sclera with a double-flange polypropylene suture. Uncorrected visual acuity (UCVA), intraocular pressure (IOP), tilt, and decentration of the intraocular lens (IOL) and postoperative complications were evaluated. All 16 patients were successfully implanted with suspended CTR and IOL after femtosecond laser assisted surgery. Visual acuity improved significantly after surgery (p < 0.01). At 1 month, 3 months and 6 months postoperatively, the tilt of the IOL was 2.70 ± 0.934, 2.65 ± 0.897, and 2.66 ± 0.781, and the decentration of the IOL was 0.30 ± 0.770, 0.30 ± 0.682, and 0.29 ± 0.737; both had no statistically significant difference between the three groups. After the operation, 4 patients had hyphema and 2 patients experienced a temporary postoperative IOP increase. Only one flange was exposed one month after operation and recovered right after secondary adjustment. Femtosecond laser combined with double-flange polypropylene suture CTR suspension was effective in fixing the lens capsule to the scleral wall in cases of subluxation of lens seen in Marfan syndrome during our short-term observation. The long-term efficacy of this operation needs further observation and follow-up.


[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment].
Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.


Impaired fear conditioning in Alzheimer's disease.
Classical conditioning of the fear response is a basic form of nondeclarative (nonconscious) memory that mediates both normal and pathological responses to aversive stimuli. Because fear conditioning critically depends on the amygdala, a medial temporal lobe structure that frequently undergoes significant pathological changes early in the course of Alzheimer's disease (AD), we hypothesized that fear conditioning would be impaired in patients with mild to moderate AD. We examined simple classical fear conditioning in a group of 10 patients with probable AD and 14 demographically matched, neurologically intact elderly controls. During conditioning, one stimulus (e.g. a green rectangle, the conditioned stimulus (CS+)), was paired with an aversive stimulus (a loud noise, the unconditioned stimulus (US)) using a partial reinforcement conditioning schedule. The opponent color (e.g. red rectangle), the CS-, was never paired with the US. The elderly controls acquired robust fear responses as demonstrated by their differential skin-conductance responses to the CS+ and CS-. In contrast, the AD group showed a marked impairment in conditioning, failing to exhibit significant conditioned fear responses. This failure to acquire conditioned responses could not be attributed to diminished responding by patients, relative to controls, to the aversive US. The results indicate that fear conditioning, an amygdala-dependent form of memory, is impaired in AD. These findings complement previous reports of impairments in declarative emotional memory in AD by demonstrating that a basic form of nondeclarative emotional memory is also impaired in AD.


[Students' evaluation of a new teaching methodology of Pediatric Nursing].
This article includes some considerations about teaching Pediatric Nursing to undergraduate students so as to justify instructors' change in attitude toward the teaching-learning process and focus evaluation made by six groups of students on the new method employed. On the whole, the students' attitude was more positive than when the traditional method was employed; they were more interested in Pediatric Nursing and showed better understanding of children's needs.


Chronic depletion of glutathione (GSH) and minimal modification of LDL in vivo: its prevention by glutathione mono ester (GME) therapy.
A decline in reduced glutathione (GSH) level is associated with aging and free radical mediated diseases. The objective of this study was to determine whether the chronic depletion of extra cellular GSH causes oxidative damage to the circulating macromolecules such as lipoproteins. Decreased concentrations of plasma glutathione, vitamin E and ascorbic acid were recorded in the rats treated with buthionine sulfoximine (BSO), a selective GSH inhibitor. In LDL isolated from BSO-treated animals, the concentration of malondialdehyde (MDA) and conjugated dienes were significantly increased (P<0.01), whereas the levels of vitamin E were decreased (P<0.01). The analysis of total and LDL cholesterol revealed significant changes between the control and experimental groups. Of interest, altered concentrations of lyso-phosphatidyl choline (Lyso-PC) and phosphatidyl choline (PC) were recorded from the BSO mediated minimally modified LDL. A negative correlation between LDL-BDC/MDA and its antioxidant capacity was noted. Upon in vitro oxidation with CuSO(4), the electrophoretic behavior of purified LDL-apoprotein-B on agarose gel showed an increased mobility in BSO-treated rats, indicative of in vivo modification of LDL to become susceptible for in vitro oxidation. The increased mobility of LDL (after in vitro oxidation) isolated from the BSO-treated animals correlates with a decrease in its amino groups, as determined by the trinitrobenzene sulfonic acid (TNBS) reactants. However, the mobility of LDL molecule was not altered due to BSO treatment in vivo. Interestingly, the minimal modification on LDL does not lead to any vascular damage in the dorsal aorta of the rats injected with BSO. The administration of glutathione monoester (GME), at a dose of 5 mmol/kg body weight, twice a day, for 30 days, to animals treated with l-buthionine-SR-sulfoximine (BSO, 4 mmol/kg body weight, twice a day, for 30 days) normalized the antioxidant status and prevented the minimal modifications on LDL. Thus, increasing the cellular GSH levels may trigger beneficial effects against oxidative stress.


Efficacy of using a hydrodebrider and of citric acid/zwitterionic surfactant on a Staphylococcus aureus bacterial biofilm in the sheep model of rhinosinusitis.
Biofilms in chronic rhinosinusitis (CRS) patients are associated with recalcitrant disease patterns. Citric acid/zwitterionic surfactant (CAZS) has been shown to have significant efficacy at in vitro biofilm eradication. Unique hydrodebrider systems have been shown to have effective antibiofilm efficacy. The aim of this study was to evaluate the efficacy of the CAZS/hydrodebrider treatment on Staphylococcus aureus biofilms in the sheep model of CRS. Forty-two sheep frontal sinuses were inoculated with S. aureus, followed by 7 days of biofilm growth. Sinuses were randomized to one of nine treatment groups: control, hydrodebrider with saline or CAZS (killed on day 0 or day 7 posttreatment), CAZS, or saline flush (killed on day 0 or day 7 posttreatment). Confocal scanning laser microscopy (CSLM) was used to confirm extent of biofilm reduction. Samples of each sinus were taken, assessing cilia morphology using electron microscopy. A mean of 37.22 ± 9.65% of control (no treatment) CSLM images taken showed biofilms. Both CAZS flush and CAZS/hydrodebrider treatments showed initial improvements in biofilms but biofilm regrowth followed treatment, 14.74 ± 9.58% to 18.91 ± 12.14% and 15.60 ± 13.92% to 24.70 ± 3.66%, respectively (p > 0.05). Saline/hydrodebrider treatments showed a nonsignificant improvement in biofilm treatment, which was maintained, 18.34 ± 11.85% to 12.04 ± 10.28% (p > 0.05). Cilial morphology grade was significantly worse in the CAZS treatment groups (p < 0.05). CAZS solution (with and without a hydrodebrider system) can significantly adversely affect cilia morphology. The hydrodebrider system, when combined with saline, may be a useful treatment adjunct for mucosal biofilms.


Surgical anatomy of sensory portion of superficial fibular nerve for harvesting nerve grafts from fetuses.
The use of superficial fibular nerve (Sfn) as a potential donor nerve in nerve grafting has been introduced. The limited availability of donor nerves has paved the way for nerve allografting. We studied the sensory portion of Sfn in 60 limbs from 30 fetuses. Three distinct patterns of the nerve were designated as Types 1, 2, and 3 by us. Type 1 (66.67%) comprised Sfn piercing fascia cruris then branching into Mdn and Idn. Type 2 (21.67%) was a pattern where Sfn penetrated deep fascia then continued undivided over the dorsum of foot. Type 3 (11.67%) was where Mdn and Idn penetrated deep fascia independently. The study provided quantitative measurement data of the sensory portion of Sfn and its branching nerves with respect to osseous landmarks like the head of fibula and the malleoli. Such data may be of help in defining nerve segments suitable for harvesting in nerve grafts from fetuses.


Comparative trial of the use of antiplatelet and oral anticoagulant in thrombosis prophylaxis in patients undergoing total cavopulmonary operation with extracardiac conduit: echocardiographic, tomographic, scintigraphic, clinical and laboratory analysis.
To compare the efficacy of aspirin and warfarin for prophylaxis of thrombosis in patients undergoing total cavopulmonary anastomosis. Evaluate whether coagulation factors (VII, VIII and protein C), clinical data, fenestration or hemodynamic factors, interfere with postoperative thrombosis. A prospective, randomized study of 30 patients, randomized into Group I (Warfarin) and Group II (AAS), underwent total cavopulmonary shunt with extracardiac conduit, between 2008 and 2011, with follow-up by clinical visits to evaluate side effects and adhesion. Performed transesophageal echocardiography in post operatory time, 3, 6,12 and 24 months; angiotomography at 6, 12 and 24 months to evaluate changes in the internal tube wall or thrombi and pulmonary scintigraphy to evaluate possible PTE. Two deaths in group I; 33.3% of patients had thrombus (46.7% in Group II). The previous occurrence of thrombus and low levels of coagulation protein C were the only factors that influenced the time free of thrombus (P=0.035 and 0.047). Angiotomographic evaluation: 35.7% in group II presented material accumulation greater than 2 mm (P=0.082). Scintigraphy: two patients had PTE in group II. Five patients had difficulty to comply with the treatment, 4 in group I with INR ranging from 1 to 6.4. The previous occurrence of thrombus is a risk factor for thrombosis in the postoperative period. Patients using AAS tend to deposit material in the tube wall. The small sample size did not allow to conclude which is the most effective drug in the prevention of thrombosis in this population.


Pigmented pyogenic granuloma of the cornea and conjunctiva: a rare bilateral presentation.
Pyogenic granuloma, also known as lobular capillary hemangioma, is a benign vascular lesion that primarily affects the skin and mucous membranes. It is not pyogenic; nor is it granulomatous. It typically arises in response to local trauma or surgery, irritation, hormonal changes, or chronic inflammation, and it sometimes occurs spontaneously. The occurrence of pigmented pyogenic granuloma in the conjunctiva and cornea without any history of trauma or surgery is extremely rare, particularly in children. We report the clinical presentation, diagnostic evaluation, and successful management of bilateral biopsy-proven conjunctival and corneal pigmented isolated pyogenic granuloma in an 11-year-old girl. No signs of recurrence were seen at the 3-months follow-up.


Evaluating backscattering polarized light imaging microstructural mapping capabilities through neural tissue and analogous phantom imaging.
Knowledge of fiber microstructure and orientation in the brain is critical for many applications. Polarized light imaging (PLI) has been shown to have potential for better understanding neural fiber microstructure and directionality due to the anisotropy in myelin sheaths surrounding nerve fibers of the brain. Continuing to advance backscattering based PLI systems could provide a valuable avenue for in vivo neural imaging. To assess the potential of backscattering PLI systems, the ability to resolve crossing fibers, and the sensitivity to fiber inclination and curvature are considered across different imaging wavelengths. Investigation of these areas of relative uncertainty is undergone through imaging potential phantoms alongside analogous regions of interest in fixed ferret brain samples with a five-wavelength backscattering Mueller matrix polarimeter. Promising phantoms are discovered for which the retardance, diattenuation and depolarization mappings are derived from the Mueller matrix and studied to assess the sensitivity of this polarimeter configuration to fiber orientations and tissue structures. Rich avenues for future study include further classifying this polarimeter's sensitivity to fiber inclination and fiber direction to accurately produce microstructural maps of neural tissue.


[Glycemia and glycosuria in the search for new energy sources for calves].
Monosaccharide (glucose), disaccharide (saccharose hydrolysate) and polysaccharide (maltodextrin KMS-X 70) were administered perorally to the calves of three age categories (pre-rumination, transition, rumination period) after 12-hour fasting. The following characteristics were investigated: glycaemia, glycosuria, lactic acid concentration, plasma osmolality, hematocrit value, net acid-base secretion and excrement dry matter. The degree of saccharide utilization was evaluated from glycaemia, glycosuria and clinical condition. The administration of maltodextrins to calves at the age of two to three weeks was not found convenient. The absorption of saccharose (hydrolyzate depended strongly on age. The saccharose hydrolyzate dose of 2.5 g per kg l. w. was calculated with respect to glycaemia and glycosuria, but not to the excrement dry matter content. In comparison with glucose absorption, saccharose hydrolyzate seems to be a convenient energy source for calves of different age categories.


Early social communication development in infants with autism spectrum disorder.
Social-communication differences are a robust and defining feature of autism spectrum disorder (ASD) but identifying early points of divergence in infancy has been a challenge. The current study examines social communication in 9- to 12-month-old infants who develop ASD (N = 30; 23% female; 70% white) compared to typically developing (TD) infants (N = 94, 38% female; 88% white). Results demonstrate that infants later diagnosed with ASD were already exhibiting fewer social-communication skills using eye gaze, facial expression, gestures, and sounds at 9 months (effect size: 0.42-0.89). Moreover, three unique patterns of change across distinct social-communication skills were observed within the ASD group. This study documents that observable social-communication differences for infants with ASD are unfolding by 9 months, pointing to a critical window for targeted intervention.


Epidemiology of Burns in Rural Bangladesh: An Update.
Each year, approximately 265,000 deaths occur due to burns on a global scale. In Bangladesh, around 173,000 children under 18 sustain a burn injury. Since most epidemiological studies on burn injuries in low and middle-income countries are based on small-scale surveys or hospital records, this study aims to derive burn mortality and morbidity measures and risk factors at a population level in Bangladesh. A household survey was conducted in seven rural sub-districts of Bangladesh in 2013 to assess injury outcomes. Burn injuries were one of the external causes of injury. Epidemiological characteristics and risk factors were described using descriptive as well as univariate and multivariate logistic regression analyses. The overall mortality and morbidity rates were 2 deaths and 528 injuries per 100,000 populations. Females had a higher burn rate. More than 50% of injuries were seen in adults 25 to 64 years of age. Most injuries occurred in the kitchen while preparing food. 88% of all burns occurred due to flame. Children 1 to 4 years of age were four times more likely to sustain burn injuries as compared to infants. Age-targeted interventions, awareness of first aid protocols, and improvement of acute care management would be potential leads to curb death and disability due to burn injuries.


A marketing clinical doctorate programs.
Over the past decade, clinical doctorate programs in health disciplines have proliferated amid both support and controversy among educators, professional organizations, practitioners, administrators, and third-party payers. Supporters argue that the explosion of new knowledge and increasing sophistication of technology have created a need for advanced practice models to enhance patient care and safety and to reduce costs. Critics argue that necessary technological advances can be incorporated into existing programs and believe that clinical doctorates will increase health care costs, not reduce them. Despite the controversy, many health disciplines have advanced the clinical doctorate (the most recent is the doctor of nursing practice in 2004), with some professions mandating the doctorate as the entry-level degree (i.e., psychology, pharmacy, audiology, and so on). One aspect of the introduction of clinical doctoral degrees has been largely overlooked, and that is the marketing aspect. Because of marketing considerations, some clinical doctorates have been more successfully implemented and accepted than others. Marketing is composed of variables commonly known as "the four P's of marketing": product, price, promotion, and place. This report explores these four P's within the context of clinical doctorates in the health disciplines.


Sleep-Time Ambulatory BP Is an Independent Prognostic Marker of CKD.
The prognostic value of clinic and ambulatory BP in predicting incident CKD and whether CKD risk reduction associates with progressive treatment-induced decrease of clinic, awake, or asleep BP are unknown. We prospectively evaluated 2763 individuals without CKD, 1343 men and 1420 women (mean±SD age: 51.5±14.3 years old), with baseline ambulatory BP ranging from normotension to hypertension. On recruitment and annually thereafter (more frequently if hypertension treatment was adjusted on the basis of ambulatory BP), we simultaneously monitored BP and physical activity (wrist actigraphy) for 48 hours to accurately derive individualized mean awake and asleep BP. During a median 5.9-year follow-up, 404 participants developed CKD. Mean asleep systolic BP was the most significant predictor of CKD in a Cox proportional hazard model adjusted for age, diabetes, serum creatinine concentration, urinary albumin concentration, previous cardiovascular event, and hypertension treatment time (on awakening versus at bedtime; per 1-SD elevation: hazard ratio, 1.44; 95% confidence interval, 1.31 to 1.56; P<0.001). The predictive values of mean clinic BP and mean awake or 48-hour ambulatory BP was not significant when corrected by mean asleep BP. Analyses of BP changes during follow-up revealed 27% reduction in the risk of CKD per 1-SD decrease in mean asleep systolic BP, independent of changes in mean clinic BP or awake ambulatory BP. In conclusion, sleep-time BP is a highly significant independent prognostic marker for CKD. Furthermore, progressive treatment-induced decrease of asleep BP, a potential therapeutic target requiring ambulatory BP evaluation, might be a significant method for reducing CKD risk.


Gradient-based optimization of hyperparameters for base-pairing profile local alignment kernels.
We have recently proposed novel kernel functions, called base-pairing profile local alignment (BPLA) kernels for discrimination and detection of functional RNA sequences using SVMs. We employ STRAL's scoring function which takes into account sequence similarities as well as upstream and downstream base-pairing probabilities, which enables us to model secondary structures of RNA sequences. In this paper, we develop a method for optimizing hyperparameters of BPLA kernels with respect to discrimination accuracy using a gradient-based optimization technique. Our experiments show that the proposed method can find a nearly optimal set of parameters much faster than the grid search on all parameter combinations.


Video Summarization Through Reinforcement Learning With a 3D Spatio-Temporal U-Net.
Intelligent video summarization algorithms allow to quickly convey the most relevant information in videos through the identification of the most essential and explanatory content while removing redundant video frames. In this paper, we introduce the 3DST-UNet-RL framework for video summarization. A 3D spatio-temporal U-Net is used to efficiently encode spatio-temporal information of the input videos for downstream reinforcement learning (RL). An RL agent learns from spatio-temporal latent scores and predicts actions for keeping or rejecting a video frame in a video summary. We investigate if real/inflated 3D spatio-temporal CNN features are better suited to learn representations from videos than commonly used 2D image features. Our framework can operate in both, a fully unsupervised mode and a supervised training mode. We analyse the impact of prescribed summary lengths and show experimental evidence for the effectiveness of 3DST-UNet-RL on two commonly used general video summarization benchmarks. We also applied our method on a medical video summarization task. The proposed video summarization method has the potential to save storage costs of ultrasound screening videos as well as to increase efficiency when browsing patient video data during retrospective analysis or audit without loosing essential information.


The response of creatine kinase specific activity in rat pituitary to estrogenic compounds and vitamin d less-calcemic analogs.
We examined the response of rat female pituitary at different metabolic stages to treatments with estrogenic compounds and vitamin D analogs. Immature or ovariectomized (Ovx) female rats responded by increased creatine kinase specific activity (CK) to estradiol-17beta (E(2)), genistein (G), daidzein (D), biochainin A (BA), quecertin (Qu), carboxy- G (cG), carboxy- BA (cBA), and raloxifene (Ral). The response was inhibited when Ral was injected together with the estrogens. CK was increased when hormones were injected daily into Ovx rats for 4 different time periods. Pretreatment with the less-calcemic vitamin D analogs JK 1624 F(2)-2 (JKF) or QW 1624 F(2)-2 (QW) followed by estrogenic injection resulted in increased response and sensitivity to E(2) and loss of inhibition of E(2) by Ral. CK was also increased by feeding with E(2) or licorice or its components dose- and time- dependent in immature or Ovxrats. Diabetic female rats did not respond to increased doses of E(2). In conclusion, rat female pituitary is estrogens-responsive organ, suggesting to considerits response for HRT in postmenopausal women for both beneficial and hazardous aspects.


[The influence of vehicles on environment in Bashkortostan].
The article deals with the problem of air pollution by vehicles in towns of Bashkortostan Republic. Significant share of extremely toxic chemicals (benzpyrene, alkylbenzenes, naphthalenes) was proved to be released into atmosphere with waste gas. Environment is polluted with vehicles waste: exhaust tires, batteries, oil, waters. The authors suggest measures aimed to lower considerably the influence of vehicles on environment.


Reliability, validity, and classification accuracy of a Spanish translation of a measure of DSM-IV diagnostic criteria for pathological gambling.
The aim of this study was to measure the reliability, validity, and classification accuracy of a Spanish translation of a measure of DSM-IV diagnostic criteria for Pathological Gambling (PG). Participants were 263 male and 23 female patients seeking treatment for PG and a matched non-psychiatric control sample of 259 men and 24 women. A Spanish translation of a 19-item measure of DSM-IV diagnostic criteria for PG (Stinchfield 2003) was administered along with other validity measures. The DSM-IV diagnostic criteria were found to be internally consistent with a coefficient alpha of .95 in the combined sample. Evidence of satisfactory convergent validity included moderate to high correlations with other measures of problem gambling. Using the standard DSM-IV cut-score of five, the ten criteria were found to yield satisfactory classification accuracy results with a high hit rate (.95), high sensitivity (.92), high specificity (.99), low false positive (.01), and low false negative rate (.08). Lowering the cut score to four resulted in modest improvements in classification accuracy and reduced the false negative rate from .08 to .05. The Spanish translation of a measure of DSM-IV diagnostic criteria for PG demonstrated satisfactory psychometric properties and a cut score of four improved diagnostic precision.


Selenium content of some foodstuffs and other environmental samples in a mineralized area of Italy.
No data are available on Selenium concentration in the Italian environment in spite of its importance as an essential and toxic element. In order to get some information about the concentration and distribution of this element in the environment and in the food-chain, a survey has been made in the Monte Amiata area (Toscana, Italy). Such an area was selected for this study owing to its large mineralization due to many elements (e.g. Fe, Cu, Ag, Sb and particularly Hg). The selenium content has been determined by thermal neutron activaltion analysis and a large volume high-resolution Ge-Li gamma ray spectrometer connected on line to a DEC PDP 8/L computer. The instrumental method requires neither a chemical separation technique nor a pre-or post-concentration of Selenium. The Selenium concentration for wet weight in foodstuffs ranges between a value of 0.008 ppm in milk and a value of 0.2 ppm in chicken. The average Se intake for the population living in the area under investigation has been also estimated. A critical discussion of the data is reported together with a comparison with the Se concentration values referring to other countries.


[Monoclonal antibody UW 21/123: clinical use and diagnostic specificity in head and neck cancers].
In addition to the originally described monoclonal antibody (MAB) against laryngeal carcinoma cells (Arch. Otorhinolaryngol. 233 (1981) 161) a new MAB was induced by means of somatic cell hybridisation techniques. The MAB UW 21/123 enables recognition of a group of squamous cell carcinomas of the head and neck. An in-vitro assay was designed allowing clinical diagnosis of malignancy in 18% out of 211 tumour patients.


pSTAT5 is associated with improved survival in patients with thick or ulcerated primary cutaneous melanoma.
Identifying prognostic biomarkers to predict clinical outcomes in stage I and II cutaneous melanomas could guide the clinical application of adjuvant and neoadjuvant therapies. We aimed to investigate the prognostic value of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) as a biomarker in early-stage melanoma. This study evaluated all initially staged Ib and II melanoma patients undergoing sentinel node biopsy at a tertiary centre in Brisbane, Australia between 1994 and 2007, with survival data collected from the Queensland Cancer Registry. Primary melanoma tissue from 189 patients was analysed for pSTAT5 level through immunohistochemistry. Cox regression modelling, with adjustment for sex, age, ulceration, anatomical location, and Breslow depth, was applied to determine the association between pSTAT5 detection and melanoma-specific survival. Median duration of follow-up was 7.4 years. High pSTAT5 detection was associated with ulceration and increased tumour thickness. However, multivariate analysis indicated that high pSTAT5 detection was associated with improved melanoma-specific survival (hazard ratio: 0.15, 95% confidence interval: 0.03-0.67) as compared to low pSTAT5 detection. This association persisted when pSTAT5 detection was limited to immune infiltrate or the vasculature, as well as when sentinel node positivity was accounted for. In this cohort, staining for high-pSTAT5 tumours identified a subset of melanoma patients with increased survival outcomes as compared to low-pSTAT5 tumours, despite the former having higher-risk clinicopathological characteristics at diagnosis. pSTAT5 is likely an indicator of local immune activation, and its detection could represent a useful tool to stratify the risk of melanoma progression.


Monte Carlo algorithms for Brownian phylogenetic models.
Brownian models have been introduced in phylogenetics for describing variation in substitution rates through time, with applications to molecular dating or to the comparative analysis of variation in substitution patterns among lineages. Thus far, however, the Monte Carlo implementations of these models have relied on crude approximations, in which the Brownian process is sampled only at the internal nodes of the phylogeny or at the midpoints along each branch, and the unknown trajectory between these sampled points is summarized by simple branchwise average substitution rates. A more accurate Monte Carlo approach is introduced, explicitly sampling a fine-grained discretization of the trajectory of the (potentially multivariate) Brownian process along the phylogeny. Generic Monte Carlo resampling algorithms are proposed for updating the Brownian paths along and across branches. Specific computational strategies are developed for efficient integration of the finite-time substitution probabilities across branches induced by the Brownian trajectory. The mixing properties and the computational complexity of the resulting Markov chain Monte Carlo sampler scale reasonably with the discretization level, allowing practical applications with up to a few hundred discretization points along the entire depth of the tree. The method can be generalized to other Markovian stochastic processes, making it possible to implement a wide range of time-dependent substitution models with well-controlled computational precision. The program is freely available at www.phylobayes.org.


Meningoencephalitis caused by pathogenic Sarcocystis species in a naturally infected sheep in Turkey.
A 3-year-old sheep was examined after an acute onset of hind limb paralysis and ataxia. At necropsy, central nervous system, pulmonary and intestinal hyperaemia and ecchymoses in the aortic arch were observed. Main microscopic lesions were confined to the heart, cerebrum and cerebellum. There were a multifocal mild myocarditis and nonsuppurative meningoencephalitis together with protozoal cysts in the heart and the brain. Protozoal cystic structures were observed within many of the myocardial fibers as well as in the cerebrum and cerebellum. Using light microscopy it could not be morphologically determined whether these organisms were Toxoplasma (T.) gondii or Neospora (N.) caninum. Additional diagnostic methods like immunohistochemistry and polymerase chain reaction provided differentiation of Sarcocystis from T. gondii and N. caninum. Transmission electron microscopy demonstrated characteristic features of Sarcocystis sp. as previously described. This is the first confirmed diagnosis of Sarcocystis sp. in the central nervous system of a sheep from Turkey.


Effects on heat tolerance of physical training in water and on land.
A 4-wk training program was undertaken by 15 untrained non-heat-acclimated males who were divided into three groups matched on maximal aerobic capacity (VO2max) and trained either in water or on land to determine how physical training (PT) in these different media affects heat tolerance. Subjects trained on a cycle ergometer for 1 h/day, 5 days/wk at 75% VO2max, with the exercise intensity progressively increased to maintain a constant training stimulus. Group I exercised on land, whereas groups II and III exercised while immersed to the neck in water of either 32 degrees C (II) or 20 degrees C (III). Daily exercise increased core temperature (Tc) in groups I and II but not in group III. Training elicited similar increases (approximately 15%) in VO2max in the three groups. Before and after PT, all subjects exercised at approximately 30% VO2max for 3 h at 49 degrees C, 20% rh. Compared with before training, groups I and II showed a decrease in final Tc and heart rate (HR) in the posttraining heat exposure. Sweat rate increased 25% in group II but remained the same in group I. Group III demonstrated a decrease in final HR, but final Tc was higher than before training. Sweat rate did not increase in group III and was lower than the other groups. It was concluded that PT can improve the cardiovascular response to dry heat without affecting thermoregulatory capacity. PT appears to enhance heat tolerance only if Tc is permitted to rise during exercise, thus stimulating the temperature-regulating center for heat dissipation.


Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis.
Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the αV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to prevent cellular damage in cerebrovascular disease.


Crlz-1 Controls Germinal Center Reaction by Relaying a Wnt Signal to the Bcl-6 Expression in Centroblasts during Humoral Immune Responses.
Crlz-1 was expressed along with Wnt3a in the rapidly proliferating centroblasts within the dark zone of germinal center (GC) during humoral immune responses. Significantly, Crlz-1 relayed a Wnt/β-catenin signal to the expression of Bcl-6, the master regulator of centroblasts, by mobilizing the cytoplasmic CBFβ into the nucleus to allow Runx/CBFβ heterodimerization and its subsequent binding to the Bcl-6 promoter. The knockdown of Crlz-1 or β-catenin, as well as inhibition of Wnt signaling in the centroblasts, led to the decreased expression of Bcl-6 and, thereby, the altered expression of its various target genes, resulting in their diminished proliferation. Consistently, the administration of Wnt inhibitors into the immunized mice impaired or abolished GC reaction, with concomitant decreases of Crlz-1 and Bcl-6 expression and, thus, centroblastic proliferation. Our observation that Wnt/β-catenin signaling via Crlz-1 regulates GC reaction would suggest developmental strategies for vaccine adjuvants and cancer therapeutics because both immune efficacy and accidental lymphoma depend on GC reaction. Our studies of Crlz-1 were performed using human cell lines, mice, and their primary cells.


PLK1 Inhibition Induces Immunogenic Cell Death and Enhances Immunity against NSCLC.
PLK1 inhibitors were shown, in vitro and in vivo, to possess inhibitory activities against non-small cell lung cancer (NSCLC), and such inhibition has been proven by clinical trials. However, it remains unclear whether and how the immune microenvironment is associated with the action. In this study, we found that inhibiting PLK1 could alter the tumor immune microenvironment by increasing DC maturation, and enriching T cells infiltration. PLK1 inhibitors, serving as immunogenic cell death (ICD) inducers, indirectly activated DCs, instead of directly acting on DC cells, through the surface expression of costimulatory molecules on and enhanced phagocytosis by DCs. Furthermore, upon targeting PLK1, tumor cells that had undergone ICD were converted into an endogenous vaccine, which triggered the immune memory responses and protected the mice from tumor challenge. Collectively, these results suggested that the PLK1 inhibitor might function as an immune modulator in antitumor treatment.


SANASA Capivari II - the first full-scale municipal membrane bioreactor in Latin America.
The macro region of Campinas (Brazil) is rapidly evolving with new housing developments and industries, creating the challenge of finding new ways to treat wastewater to a quality that can be reused in order to overcome water scarcity problems. To address this challenge, SANASA (a publicly owned water and wastewater concessionaire from Campinas) has recently constructed the 'EPAR (Water Reuse Production Plant) Capivari II' using the GE ZeeWeed 500D(®) ultrafiltration membrane system. This is the first large-scale membrane bioreactor (MBR) system in Latin America with biological tertiary treatment capability (nitrogen and phosphorus removal), being able to treat an average flow of 182 L/s in its first phase of construction. The filtration system is composed of three membrane trains with more than 36,000 m(2) of total membrane filtration area. The membrane bioreactor (MBR) plant was commissioned in April 2012 and the permeate quality has exceeded expectations. Chemical oxygen demand (COD) removal rates are around and above 97% on a consistent basis, with biochemical oxygen demand (BOD5) and NH3 (ammonia) concentrations at very low levels, and turbidity lower than 0.3 nephelometric turbidity unit (NTU). Treated effluent is sent to a water reuse accumulation tank (from where will be distributed as reuse water), and the excess is discharged into the Capivari River.


'The Healthy Migrant Effect' for Mental Health in England: Propensity-score Matched Analysis Using the EMPIRIC Survey.
Evidence has demonstrated that immigrants have a mental health advantage over the indigenous population of developed countries. However, much of the evidence-base demonstrating this mental health advantage is susceptible to confounding and inadequate adjustment across immigrant and non-immigrant groups preventing a rigorous assessment of a 'healthy migrant effect'. To compare the risk of common mental disorders in the immigrant population compared to the non-immigrant population in ethnic minority groups in England. A propensity-score matched analysis was carried out to adequately balance immigrant and non-immigrant groups for known confounders using the EMPIRIC national survey of Black-Caribbean, Indian, Pakistani and Bangladeshi groups. The mental health of participants was assessed using the validated Revised Clinical Interview Schedule tool. Immigrant participants were significantly less likely to have a common mental disorder than non-immigrant participants; OR = 0.47, (95% CI 0.40, 0.56). The results from this study demonstrate that a mental health advantage exists in ethnic minority immigrants compared to non-immigrants when balancing the two groups for confounding factors. This may be due to immigrants possessing certain personality traits, such as "psychological hardiness", that the migration process may select for.


Environmental Metagenomic Assemblies Reveal Seven New Highly Divergent Chlamydial Lineages and Hallmarks of a Conserved Intracellular Lifestyle.
The Chlamydiae phylum exclusively encompasses bacteria sharing a similar obligate intracellular life cycle. Existing 16S rDNA data support a high diversity within the phylum, however genomic data remain scarce owing to the difficulty in isolating strains using culture systems with eukaryotic cells. Yet, Chlamydiae genome data extracted from large scale metagenomic studies might help fill this gap. This work compares 33 cultured and 27 environmental, uncultured chlamydial genomes, in order to clarify the phylogenetic relatedness of the new chlamydial clades and to investigate the genetic diversity of the Chlamydiae phylum. The analysis of published chlamydial genomes from metagenomics bins and single cell sequencing allowed the identification of seven new deeply branching chlamydial clades sharing genetic hallmarks of parasitic Chlamydiae. Comparative genomics suggests important biological differences between those clades, including loss of many proteins involved in cell division in the genus Similichlamydia, and loss of respiratory chain and tricarboxylic acid cycle in several species. Comparative analyses of chlamydial genomes with two proteobacterial orders, the Rhizobiales and the Rickettsiales showed that genomes of different Rhizobiales families are much more similar than genomes of different Rickettsiales families. On the other hand, the chlamydial 16S rRNAs exhibit a higher sequence conservation than their Rickettsiales counterparts, while chlamydial proteins exhibit increased sequence divergence. Studying the diversity and genome plasticity of the entire Chlamydiae phylum is of major interest to better understand the emergence and evolution of this ubiquitous and ancient clade of obligate intracellular bacteria.


Intracranial pressure monitoring in normal dogs using subdural and intraparenchymal miniature strain-gauge transducers.
Monitoring of intracranial pressure (ICP) is a critical component in the management of intracranial hypertension. Safety, efficacy, and optimal location of microsensor devices have not been defined in dogs. Assessment of ICP using a microsensor transducer is feasible in anesthetized and conscious animals and is independent of transducer location. Intraparenchymal transducer placement is associated with more adverse effects. Seven adult, bred-for-research dogs. In a prospective investigational study, microsensor ICP transducers were inserted into subdural and intraparenchymal locations at defined rostral or caudal locations within the rostrotentorial compartment under general anesthesia. Mean arterial pressure and ICP were measured continuously during physiological maneuvers, and for 20 hours after anesthesia. Baseline mean ± SD values for ICP and cerebral perfusion pressure were 7.2 ± 2.3 and 78.9 ± 7.6 mm Hg, respectively. Catheter position did not have a significant effect on ICP measurements. There was significant variation from baseline ICP accompanying physiological maneuvers (P < .001) and with normal activities, especially with changes in head position (P < .001). Pathological sequelae were more evident after intraparenchymal versus subdural placement. Use of a microsensor ICP transducer was technically straightforward and provided ICP measurements within previously reported reference ranges. Results support the use of an accessible dorsal location and subdural positioning. Transient fluctuations in ICP are normal events in conscious dogs and large variations associated with head position should be accounted for when evaluating animals with intracranial hypertension.


Improving RNA-based crop protection through nanotechnology and insights from cross-kingdom RNA trafficking.
Spray-induced gene silencing (SIGS) is a powerful and eco-friendly method for crop protection. Based off the discovery of RNA uptake ability in many fungal pathogens, the application of exogenous RNAs targeting pathogen/pest genes results in gene silencing and infection inhibition. However, SIGS remains hindered by the rapid degradation of RNA in the environment. As extracellular vesicles are used by plants, animals, and microbes in nature to transport RNAs for cross-kingdom/species RNA interference between hosts and microbes/pests, nanovesicles and other nanoparticles have been used to prevent RNA degradation. Efforts examining the effect of nanoparticles on RNA stability and internalization have identified key attributes that can inform better nanocarrier designs for SIGS. Understanding sRNA biogenesis, cross-kingdom/species RNAi, and how plants and pathogens/pests naturally interact are paramount for the design of SIGS strategies. Here, we focus on nanotechnology advancements for the engineering of innovative RNA-based disease control strategies against eukaryotic pathogens and pests.


Bringing the Nonlinearity of the Movement System to Gestural Theories of Language Use: Multifractal Structure of Spoken English Supports the Compensation for Coarticulation in Human Speech Perception.
Coarticulation is the tendency for speech vocalization and articulation even at the phonemic level to change with context, and compensation for coarticulation (CfC) reflects the striking human ability to perceive phonemic stability despite this variability. A current controversy centers on whether CfC depends on contrast between formants of a speech-signal spectrogram-specifically, contrast between offset formants concluding context stimuli and onset formants opening the target sound-or on speech-sound variability specific to the coordinative movement of speech articulators (e.g., vocal folds, postural muscles, lips, tongues). This manuscript aims to encode that coordinative-movement context in terms of speech-signal multifractal structure and to determine whether speech's multifractal structure might explain the crucial gestural support for any proposed spectral contrast. We asked human participants to categorize individual target stimuli drawn from an 11-step [ga]-to-[da] continuum as either phonemes "GA" or "DA." Three groups each heard a specific-type context stimulus preceding target stimuli: either real-speech [al] or [a], sine-wave tones at the third-formant offset frequency of either [al] or [aɹ], and either simulated-speech contexts [al] or [aɹ]. Here, simulating speech contexts involved randomizing the sequence of relatively homogeneous pitch periods within vowel-sound [a] of each [al] and [aɹ]. Crucially, simulated-speech contexts had the same offset and extremely similar vowel formants as and, to additional naïve participants, sounded identical to real-speech contexts. However, randomization distorted original speech-context multifractality, and effects of spectral contrast following speech only appeared after regression modeling of trial-by-trial "GA" judgments controlled for context-stimulus multifractality. Furthermore, simulated-speech contexts elicited faster responses (like tone contexts do) and weakened known biases in CfC, suggesting that spectral contrast depends on the nonlinear interactions across multiple scales that articulatory gestures express through the speech signal. Traditional mouse-tracking behaviors measured as participants moved their computer-mouse cursor to register their "GA"-or-"DA" decisions with mouse-clicks suggest that listening to speech leads the movement system to resonate with the multifractality of context stimuli. We interpret these results as shedding light on a new multifractal terrain upon which to found a better understanding in which movement systems play an important role in shaping how speech perception makes use of acoustic information.


Pre- and post-intervention assessment of a PMTCT-programme-strengthening initiative in a rural area of the Eastern Cape, South Africa.
The research assesses prevention-of-mother-to-child-transmission-of-HIV (PMTCT) services following implementation of programme-strengthening activities in a municipality in the Eastern Cape Province, South Africa. A pre-intervention and post-intervention design was used to conduct facility assessments and client exit interviews at baseline and after 28 months. For the facility assessments, unstructured interviews were conducted with the heads of maternity wards at each delivery facility (n = 4), nurses (n = 9) and lay counsellors (n = 18). District Health Information System (DHIS) records were used to assess changes on PMTCT-programme indicators. Observations were conducted at the fixed clinics and hospitals to determine compliance to the national criteria for PMTCT-services delivery. For the exit interviews with clients, the pre- and post-assessment samples, respectively, included women attending for antenatal care (n = 296; n = 239) as well as HIV-positive women attending for postnatal care (n = 70; n = 142). The personnel generally perceived the PMTCT services as having been strengthened as a result of the initiative and the DHIS records showed positive changes. Client exit interviews revealed significant increases in the numbers of women who: were aware of the PMTCT programme; were tested for HIV during their pregnancy; were aware of VCT before coming to the facility; knew their HIV-test result; and, had helpful pre-HIV-test and/or post-HIV-test counselling experiences. The long waiting periods at the facilities and the relatively short length of the counselling sessions remained a serious concern. Lessons learnt may help with designing strategies to expand the national programme in South Africa as well as PMTCT programmes elsewhere.


Receptors for non-MHC ligands contribute to uterine natural killer cell activation during pregnancy in mice.
Activated uterine natural killer (uNK) cells are abundant in early human and mouse decidual basalis. In mice, distinct uNK cell subsets support early endothelial tip cell induction, the pruning of new vessels and initiation of spiral arterial modification. While genetic studies indicate that NK/uNK cell activation via receptors recognizing Class I MHC-derived peptides promotes human pregnancy, roles for other activation receptors expressed by NK cells, such as the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptors (NCR) are undefined in human or mouse pregnancies. Expression of AHR and NCR1 (ortholog of human NKp46) by gestation day (gd)10.5 mouse uNK cell subsets was measured by quantitative real-time RT-PCR. Early implantation sites from mice lacking expression of either receptor were examined histologically. Gd10.5 uNK cell subsets, separated by reactivity to Dolichos biflorus agglutinin lectin, differed in relative transcript abundance for Ahr and Ncr1. Quantitative histology revealed that, in comparison to C57BL/6 controls, implant sites from gd10.5 Ahr(-/-) and gd6.5-12.5 UkCa:B6.Ncr1(Gfp/Gfp) mice had normal uNK cell abundance but the uNK cells were smaller than normal and unable to trigger spiral arterial remodeling. Whole mount immunohistochemistry comparisons of viable, gd6.5-8.5 Ncr1(Gfp/Gfp) and C57BL/6 implant sites revealed deficits in implant site angiogenesis and conceptus growth in Ncr1(Gfp/Gfp). In mice, activation of AHR and of NCR1 by endogenous, as yet undefined ligands, contributes to uNK cell activation/maturation and angiogenic functions during early to mid-gestation pregnancy. MHC-independent activation of uNK cells also likely makes critical contributions to human pregnancy success.


Effect of a supplement containing trans-10,cis-12 conjugated linoleic acid on the performance of dairy ewes fed 2 levels of metabolizable protein and at a restricted energy intake.
Trans-10,cis-12 conjugated linoleic acid (CLA) inhibits milk fat synthesis in dairy ewes, but the effects under varying dietary metabolizable protein (MP) levels when energy-limited diets are fed have not been examined. The objectives of the study were to evaluate the response of lactating dairy ewes to CLA supplementation when fed diets limited in metabolizable energy (ME) and with either a low or high MP content. Twelve multiparous ewes in early lactation were randomly allocated to 1 of 4 dietary treatments: a high MP (110% of daily MP requirement) or low MP (93% of daily MP requirement) diet unsupplemented or supplemented with a lipid-encapsulated CLA to provide 2.4 g/d of trans-10,cis-12 CLA, in each of 4 periods of 25 d each in a 4×4 Latin square design. All diets were restricted to supply each ewe with 4.6 Mcal of ME/d (equivalent to 75% of ME requirement). Supplementation with CLA decreased milk fat percentage and yield by 33% and 24%, respectively, and increased milk, milk protein, and lactose yields by 16, 13, and 17%, respectively. Feeding the high MP diet increased the yields of milk, fat, protein, and lactose by 18, 15, 19, and 16%, respectively. Milk fat content of trans-10,cis-12 CLA (g/100g) was 0.09 and <0.01 for the CLA-supplemented and unsupplemented ewes, respectively. Ewes supplemented with CLA had a reduced yield (mmol/d) of fatty acids of <C16, C16, and >C16, although the effect was greatest for <C16. Feeding a high MP level increased the yield of fatty acids of C16 and >C16. Plasma urea concentrations were lowest in ewes supplemented with CLA compared with those unsupplemented (6.5 vs. 7.4 mmol/L, respectively) and receiving low compared with high MP diets (5.6 vs. 8.3 mmol/L, respectively). In conclusion, dairy ewes fed energy-limited diets and supplemented with CLA repartitioned nutrients to increase yields of milk, protein, and lactose, with the response to CLA supplementation and additional MP intake being additive.


Proprietary management and higher readmission rates: A correlation.
Reducing preventable readmissions among Medicare beneficiaries is an effective way to not only reduce the exorbitantly rising cost in healthcare but also as a measure to improve the quality of patient care. Many of the previous efforts in reducing readmission rate of patients have not been very successful because of ill-defined quality measures, improper data collection methods and lack of effective strategies based on data driven solutions. In this study, we analyzed the readmission data of patients for six major diseases including acute myocardial infarction (AMI), heart failure (HF), coronary artery bypass graft (CABG), pneumonia (PN), chronic obstructive pulmonary disease (COPD), and total hip arthroplasty and/or total knee arthroplasty (THA/TKA) from the Center for Medicare and Medicaid Readmissions Reduction Program (HRRP) program for the period 2012-2015 in context with the ownership structure of the hospitals. Our analysis demonstrates that the readmission rates of patients were statistically higher in proprietary (for profit) hospitals compared to the government and non-profit hospitals which was independent of their geographical distribution across all six major diseases. This finding we believe has strong implications for policy makers to mitigate any potential risks in the quality of patient care arising from unintended revenue pressure in healthcare institutions.


A case of bilateral tibial hemimelia type VIIa.
Congenital absence of tibia is a rare anomaly, and may be total or partial, unilateral or bilateral. Total absence is more frequent than partial, unilateral absence occurs more often than bilateral, with right limb more commonly affected than the left. In partial defect, almost always the distal end of the bone is affected, and of the bilateral cases, there may be total absence on both sides, or total on one side and partial on the other. Males are slightly more commonly affected than the females. Though, the family history is usually negative for congenital abnormalities and other diseases, there is a considerable chance of occurrence of congenital defect of the tibia or of other abnormalities, in near or remote relatives. We report a case of newborn having bilateral tibial hemimelia type VIIa.


Fields, networks, creativity and evolution.
Organisms constitute wholes as a result of a network of organizing relations between the parts. In animals, this network has a morphological as well as a psychological aspect, and it regulates morphogenesis as well as behaviour. It is pointed out that closed networks of higher order, that have the characteristics of single organisms (communities of ants, termites and bees, cases of symbiosis, and perhaps even the Earth), could also possess that regulating aspect. In the case of humans, the network can be associated with creativity and the structure of knowledge. Individuation (as defined in Jung's psychology) refers to the assimilation of the network into consciousness. The theory developed in the present paper could give rise to a multi-disciplinary approach to the study of life.


Does direct human eye contact function as a warning cue for domestic sheep (Ovis aries)?
Direct eye contact may function as a warning cue during interspecific interactions, and human staring has been shown to influence the behavior of many species. The authors used an arena test to assess whether human staring altered the behavior of domestic sheep (Ovis aries) compared with no human eye contact. Sheep glanced at the staring human's face more often in the first 2 min of the test, indicating that they perceived a difference between the human stimuli. Staring also elicited more locomotor activity and urination than averted gaze. However, there were no differences in fear-related behaviors, suggesting that a staring human did not represent a greater immediate threat than a nonwatching human. These results imply that human staring is a warning cue for domestic sheep, but no more. Without further reinforcement, sheep quickly habituated to the warning cue.


Development and application of multiprobe real-time PCR method targeting the hsp65 gene for differentiation of Mycobacterium species from isolates and sputum specimens.
We developed a multiprobe real-time PCR assay targeting hsp65 (HMPRT-PCR) to detect and identify mycobacterial isolates and isolates directly from sputum specimens. Primers and probes for HMPRT-PCR were designed on the basis of the hsp65 gene sequence, enabling the recognition of seven pathogenic mycobacteria, including Mycobacterium tuberculosis, M. avium, M. intracellulare, M. kansasii, M. abscessus, M. massiliense, and M. fortuitum. This technique was applied to 24 reference and 133 clinical isolates and differentiated between all strains with 100% sensitivity and specificity. Furthermore, this method was applied to sputum specimens from 117 consecutive smear-positive patients with smear results of from a trace to 3+. These results were then compared to those obtained using the rpoB PCR-restriction analysis method with samples from cultures of the same sputum specimens. The HMPRT-PCR method correctly identified the mycobacteria in 89 samples (76.0%, 89/117), and moreover, the sensitivity level was increased to 94.3% (50/53) for sputa with an acid-fast bacillus score equal to or greater than 2+. Our data suggest that this novel HMPRT-PCR method could be a promising approach for detecting pathogenic mycobacterial species from sputum samples and culture isolates routinely in a clinical setting.


Association of Telomere Length With Myocardial Infarction: A Prospective Cohort From the Population Based HUNT 2 Study.
As possible markers of biological age, telomere length (TL) has been associated with age-related diseases such as myocardial infarction (MI) with conflicting findings. We sought to assess the relationship between TL and risk of future MI in 915 healthy participants (51.7% women) 65 years or older from a population-based prospective cohort (the HUNT 2 study, Norway). Mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio, and log-transformed. During a mean follow up of 13.0 (SD, 3.2) years and 11,923 person-years, 82 participants were diagnosed with MI. We used Cox proportional hazard regressions to estimate hazard ratios (HR) and 95% confidence interval (CI). Relative TL was associated with age in women (P=0.01), but not in men (P=0.43). Using relative TL as a continuous variable, we observed a higher risk of MI in participants with longer telomeres with HRs of 2.46 (95% CI; 1.13 to 4.54) in men, and 2.93 (95% CI; 1.41 to 6.10) in women. Each 1-SD change in relative TL was associated with an HR of 1.54 (95% CI; 1.15 to 2.06) and 1.67 (95% CI; 1.18 to 2.37) in men and women, respectively. Compared with the bottom tertile of relative TL, HR of incident MI in top tertile was 2.71 (95% CI; 1.25 to 5.89) in men, and 3.65 (95% CI; 1.35 to 9.90) in women. Longer telomeres in healthy participants 65 years or older are associated with a high risk of incident MI. Future large scale prospective studies are needed to confirm these findings and explore the potential association between TL and MI.


The comparison of morbid obesity quality of life and body image between surgery and other treatments: A case-control study.
Morbid obesity is rising around the world. Surgery is a selective treatment intervention for it. Since most of the surgeons use weight loss for evaluating of the morbid obesity surgical outcomes and paying attention to the the quality of life (QOL) and body image evaluation are rare, this study aimed to assess the QOL and body image in pre- and postsurgery with other interventions. This case-control study was done on 200 morbidly obese patients (n = 100 in each group) who referred to the obesity clinic in Shiraz. The data were collected by Body Image Concern Inventory and 12-item Short Form Survey. The data were analyzed by t-test, Pearson correlation coefficient test, analysis of variance, and regression analysis. P = 0.05 was considered as significant. The paired t-test showed a significant difference in mean scores of body image (P < 0.001) and all dimensions of the QOL (P < 0.001) in the case and control groups. In the case group, there was a significant difference between the mean scores of the QOL and the different categories of body mass index (BMI) in postsurgery (P < 0.05) and the different mean scores of body image and the different categories of BMI in pre- and postsurgery wasn't significant (P > 0.05). Age was a predictor variable for the QOL of morbidly obese persons after surgery (P < 0.001). After surgery, men showed better QOL than women (P < 0.001). Final results indicated that body image and QOL defects caused by obesity could be more improvement after surgery. This study can promote health-care team's knowledge about holistic supporting of all dimensions' QOL of obese individuals. It is suggested that supporting interventions should be done as effective methods of maintenance for effects of weight loss methods such as surgery.


Albumin-based nanoparticles as magnetic resonance contrast agents: II. Physicochemical characterisation of purified and standardised nanoparticles.
We are developing a nanoparticulate histochemical reagent designed for histochemistry in living animals (molecular imaging), which should finally be useful in clinical imaging applications. The iterative development procedure employed involves conceptual design of the reagent, synthesis and testing of the reagent, then redesign based on data from the testing; each cycle of testing and development generates a new generation of nanoparticles, and this report describes the synthesis and testing of the third generation. The nanoparticles are based on human serum albumin and the imaging modality selected is magnetic resonance imaging (MRI). Testing the second particle generation with newly introduced techniques revealed the presence of impurities in the final product, therefore we replaced dialysis with diafiltration. We introduced further testing methods including thin layer chromatography, arsenazo III as chromogenic assay for gadolinium, and several versions of polyacrylamide gel electrophoresis, for physicochemical characterisation of the nanoparticles and intermediate synthesis compounds. The high grade of chemical purity achieved by combined application of these methodologies allowed standardised particle sizes to be achieved (low dispersities), and accurate measurement of critical physicochemical parameters influencing particle size and imaging properties. Regression plots confirmed the high purity and standardisation. The good degree of quantitative physicochemical characterisation aided our understanding of the nanoparticles and allowed a conceptual model of them to be prepared. Toxicological screening demonstrated the extremely low toxicity of the particles. The high magnetic resonance relaxivities and enhanced mechanical stability of the particles make them an excellent platform for the further development of MRI molecular imaging.


Arthroplasty in the military: a preliminary experience with ProDisc-C and ProDisc-L.
The introduction of cervical and lumbar arthroplasty has allowed for management of cervical radiculopathy and lumbar degenerative disease in patients with the preservation of motion at the affected segment. While the early clinical outcomes of this technology appear promising, it remains unclear what activity limitations should be imposed after surgery in patients with these implants. This is of particular interest in military personnel, who may be required to return to a rigorous level of activity after surgery. The goals of the FDA trials evaluating various disc arthroplasty devices were to establish safety, efficacy, and equivalency to arthrodesis. Information regarding the level of physical performance attained and restrictions or limitations is lacking, as these were outside the objectives of these trials. Nevertheless, there data are essential for the military surgeon, who is tasked with guiding the postoperative management of patients treated with arthroplasty and returning them to full duty. While there is a single report of clinical results of lumbar arthroplasty in athletes, at this writing, there are no reports of either cervical or lumbar arthroplasty in active duty military personnel. The surgical database at a single, tertiary care military treatment facility was queried for all active-duty patients who underwent placement of either a cervical or lumbar arthroplasty device over a 3-year period. The authors performed a retrospective chart review to collect patient and procedural data including blood loss, length of hospital stay, tobacco use, age, rank, complications, and ability to return to full unrestricted active duty. Arthroplasty cohorts were then compared to historical controls of arthrodesis to ascertain differences in the time required to return to full duty. Twelve patients were identified who underwent cervical arthroplasty. All patients returned to unrestricted full duty. This cohort was then compared with 12 patients who had undergone a single-level anterior cervical discectomy and fusion. The average time to return to unrestricted full duty for the arthroplasty group was 10.3 weeks (range 7-13 weeks), whereas that in the fusion group was 16.5 weeks. This difference between these 2 groups was statistically significant (p = 0.008). Twelve patients were identified who underwent lumbar arthroplasty. Ten (83%) of 12 patients in this group returned to unrestricted full duty. In patients who returned to full duty, it took an average of 22.6 weeks (range 12-29 weeks). This cohort was then compared with one in which patients had undergone anterior lumbar interbody fusion. Eight (67%) of 12 patients in the lumbar arthrodesis group returned to unrestricted full duty. In patients who returned to full duty, it took an average of 32.4 weeks (range 25-41 weeks). This difference was not statistically significant (p = 0.156). The preliminary experience with cervical and lumbar arthroplasty at the authors' institution indicates that arthroplasty is comparable with arthrodesis and may actually expedite return to active duty. Patients are capable of returning to a high level of rigorous training and physical performance. There are no apparent restrictions or limitations that are required after 3 months in the cervical patient and after 6 months in the lumbar patient. Further prospective studies with long-term follow-up are indicated and will be of value when determining the role of arthroplasty compared to arthrodesis in the active-duty population.


The Daily Activity of Patients With Heart Failure During COVID-19 Pandemic.
Sedentary behavior is thought to contribute to worsening heart failure syndromes. Here, we examined whether the shelter-in-place order during the coronavirus disease 2019 (COVID-19) pandemic changed daily activity duration, which was monitored by an implantable cardiac device-based multisensor index and alert algorithm called HeartLogic. We performed a retrospective review of the HeartLogic data from patients with heart failure managed at our clinic and compared the individual daily activity duration 90 days prior to vs. after implementation of the shelter-in-place order. The activity data were prepared by Boston Scientific. Demographic data were extracted from our electronic medical record. In total, 29 patients were included in the analysis. Among them, 14 patients did not have any significant changes in daily activity duration compared to their baseline before the shelter-in-place order (108.62 ± 45 min vs. 107.71 ± 48.6 min, P = 0.723). Among the rest 15 patients with significant changes, seven patients had a significant reduction in activity duration; meanwhile, eight patients had a significant increase in activity duration. Overall, the mean daily activity duration 90 days before and after the shelter-in-place order are 98.21 ± 60.83 min, and 100.03 ± 68.18 min (P = 0.753). No significant changes in terms of activity duration were observed in our patients during the COVID-19 pandemic.


Pharmaceutical policies: effects of restrictions on reimbursement.
Public policy makers and benefit plan managers need to restrain rising pharmaceutical drug costs while preserving access and optimizing health benefits. To determine the effects of a pharmaceutical policy restricting the reimbursement of selected medications on drug use, health care utilization, health outcomes and costs (expenditures). We searched the 14 major bibliographic databases and websites (to January 2009). Included were studies of pharmaceutical policies that restrict coverage and reimbursement of selected drugs or drug classes, often using additional patient specific information related to health status or need. We included randomised controlled trials, non-randomised controlled trials, interrupted time series (ITS) analyses, repeated measures studies and controlled before-after studies set in large care systems or jurisdictions. Two authors independently extracted data and assessed study limitations. Quantitative re-analysis of time series data was undertaken for studies with sufficient data. We included 29 ITS analyses (12 were controlled) investigating policies targeting 11 drug classes for restriction. Participants were most often senior citizens or low income adult populations, or both, in publically subsidized or administered pharmaceutical benefit plans. Impact of policies varied by drug class and whether restrictions were implemented or relaxed. When policies targeted gastric-acid suppressant and non-steroidal anti-inflammatory drug classes, decreased drug use and substantial savings on drugs occurred immediately and for up to two years afterwards, with no increase in the use of other health services (6 studies). Targeting second generation antipsychotic drugs increased treatment discontinuity and the use of other health services without reducing overall drug expenditures (2 studies). Relaxing restrictions for reimbursement of antihypertensives and statins increased appropriate use and decreased overall drug expenditures. Two studies which measured health outcomes directly were inconclusive. Implementing restrictions to coverage and reimbursement of selected medications can decrease third-party drug spending without increasing the use of other health services (6 studies). Relaxing reimbursement rules for drugs used for secondary prevention can also remove barriers to access. Policy design, however, needs to be based on research quantifying the harm and benefit profiles of target and alternative drugs to avoid unwanted health system and health effects. Health impact evaluation should be conducted where drugs are not interchangeable. Impacts on health equity, relating to the fair and just distribution of health benefits in society (sustainable access to publically financed drug benefits for seniors and low income populations, for example), also require explicit measurement.


Factors associated with early mycological clearance in HIV-associated cryptococcal meningitis.
The first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management. To determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM. Retrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models. From January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14-2.14); severe baseline intracranial pressure (≥35 cm H2O) (RR, 0.57; 95% CI, 0.33-0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39-0.95). In a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe baseline intracranial pressure were negatively associated, and thus related to failure.


Epidemiology of Invasive Early-Onset and Late-Onset Group B Streptococcal Disease in the United States, 2006 to 2015: Multistate Laboratory and Population-Based Surveillance.
Invasive disease owing to group B Streptococcus (GBS) remains an important cause of illness and death among infants younger than 90 days in the United States, despite declines in early-onset disease (EOD; with onset at 0-6 days of life) that are attributed to intrapartum antibiotic prophylaxis (IAP). Maternal vaccines to prevent infant GBS disease are currently under development. To describe incidence rates, case characteristics, antimicrobial resistance, and serotype distribution of EOD and late-onset disease (LOD; with onset at 7-89 days of life) in the United States from 2006 to 2015 to inform IAP guidelines and vaccine development. This study used active population-based and laboratory-based surveillance for invasive GBS disease conducted through Active Bacterial Core surveillance in selected counties of 10 states across the United States. Residents of Active Bacterial Core surveillance areas who were younger than 90 days and had invasive GBS disease in 2006 to 2015 were included. Data were analyzed from December 2017 to April 2018. Group B Streptococcus isolated from a normally sterile site. Early-onset disease and LOD incidence rates and associated GBS serotypes and antimicrobial resistance. The Active Bacterial Core surveillance program identified 1277 cases of EOD and 1387 cases of LOD. From 2006 to 2015, EOD incidence declined significantly from 0.37 to 0.23 per 1000 live births (P < .001), and LOD rates remained stable (mean, 0.31 per 1000 live births). Among the mothers of 1277 infants with EOD, 617 (48.3%) had no indications for IAP and did not receive it, and 278 (21.8%) failed to receive IAP despite having indications. Serotype data were available for 1743 of 1897 patients (91.3%) from 7 sites that collect GBS isolates. Among patients with EOD, serotypes Ia (242 [27.3%]) and III (242 [27.3%]) were most common. Among patients with LOD, serotype III was most common (481 [56.2%]), and this increased from 2006 to 2015 from 0.12 to 0.20 cases per 1000 live births (P < .001). Serotype IV caused 53 cases (6.2%) of EOD and LOD combined. The 6 most common serotypes (Ia, Ib, II, III, IV, and V) caused 881 EOD cases (99.3%) and 853 LOD cases (99.7%). No β-lactam resistance was identified; 359 isolates (20.8%) tested showed constitutive clindamycin resistance. In 2015, an estimated 840 EOD cases and 1265 LOD cases occurred nationally. The rates of LOD among US infants are now higher than EOD rates. Combined with addressing IAP implementation gaps, an effective vaccine covering the most common serotypes might further reduce EOD rates and help prevent LOD, for which there is no current public health intervention.


Social Media and Mobile-App use for Sexual Encounters among Men Who Have Sex With Men in Puerto Rico.
To describe the use and frequency of use of mobile apps (internetand/ or smartphone-based geospatial networking apps) among men who have sex with men (MSM) and how these platforms are used to engage with sexual partners in PR. A local module including questions regarding mobile apps and sexual engagement and derived from the 2017 Puerto Rico National HIV Behavioral Surveillance System, fifth MSM cycle, was used for this analysis. A subsample of 127 eligible participants was recruited through venue-based sampling and assented to participate. Univariate analysis was used to evaluate sociodemographic and behavioral characteristics, HIV testing, and the ways in which mobile apps are used to find sexual partners. The participants' median age was 35 years, with a standard deviation of ±11.37 years. Most of our sample (97%) had had anal sex with at least 1 partner in the last 12 months, and 76% of them had had condomless anal sex. Over three fourths (81%) reported using apps for sexual encounters, while 45% stated that the most frequently used app was Grindr. Of the participants who had used apps for sexual encounters, 57% had met 5 or more sexual partners through apps in their lifetime. This study shows that there is a need for further research to understand the habits of this population in PR regarding the use of apps to find sexual partners and, also, as a possible way to develop strategies for prevention and health promotion in this group.


Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis.
To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine ("triple therapy"), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients.