Flap Reconstruction for Esophageal Perforation Complicating Anterior Cervical Spinal Fusion: An 18-year Experience.
Esophageal injury following anterior cervical discectomy and fusion (ACDF) poses a significant reconstructive challenge. Buttressing flap repairs have proven beneficial; however, there remains a paucity of evidence to guide optimal flap selection. A retrospective chart review was performed for patients who presented to the senior author with esophageal perforations after ACDF from 1995 until present. Demographic, clinical, and postoperative details were collected. Outcomes of omental flap reconstructions were compared against other flap reconstructions. A total of 13 flap reconstructions were performed in 11 patients with the following distribution: 7 free omental, 1 anterolateral thigh, 1 osteomuscular fibula, 2 radial forearm, and 2 pedicled pectoralis flaps. Patients receiving omental flap reconstructions demonstrated a significantly faster resolution of leak on contrast swallow imaging and earlier return to oral feeding compared with all other flap reconstructions (22.5 versus 268 days, respectively; P < 0.05). This relationship remained evident even when calculations excluded an outlying patient from the nonomental cohort (22.5 versus 111 days, respectively; P < 0.05). Length of hospital stay, complications, and success rates were also more favorable in the omental cohort but failed to reach statistical significance. Esophageal perforation after ACDF is an uncommon but devastating complication. The use of free omentum flap reconstruction is associated with a more rapid functional recovery and may prove beneficial in the management of these challenging cases.


Translating findings from basic fear research to clinical psychiatry in Puerto Rico.
Recent advances in the neuroscience of classical fear conditioning from both rodent and human studies are beginning to be translated to the psychiatry clinic. In particular, our understanding of fear extinction as a form of "safety learning" holds promise for the treatment of anxiety disorders in which extinction learning is thought to be compromised. The Department of Psychiatry at the UPR, School of Medicine promotes the development of innovative strategies for treating mental health problems. Given the burden resulting from anxiety disorders in Puerto Rico, and the lack of evidence-based treatment practices, there is a pressing need for a future center specializing in the treatment of anxiety related disorders. This center would also serve research and training functions, with the ultimate goal of translating extinction research into clinical practice. This review presents the current developments in extinction research and its relationship to anxiety disorders and treatment. We also analyze the available literature on the epidemiology of anxiety disorders and the existing evidence-based treatments for these conditions.


Isolated avulsion of the tibial attachment of the posterior cruciate ligament of the knee.
Of fourteen isolated avulsion fracutres of the posterior tibial attachment of the posterior cruciate ligament, one was undisplaced and five were minimally displaced. These six were treated conservatively, but four of the five displaced avulsion fractures progressed to non-union and significant functional disability. Eight displaced avulsion injuries were treated by open reduction. In four knees the fragment was sutured back to its origin on the posterior superior aspect of the tibia, and three of the these united. In two knees the fragment was large enough to fix with a screw and union ensued. There was excellent functional capacity in five of the six that united. The other two displaced fractures, treated three and seven months after injury, had open reduction and the fragments were sutured to the tibia in an advanced position. Union was obtained in both with good functional capacity.


Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells.
Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.


Nodular Fasciitis - Fine Needle Aspiration Cytology Diagnosis and Its Pitfalls, with Review of Literature.
Nodular fasciitis (NF) is a self-limiting, transient neo- plasm composed of fibroblasts and myofibroblasts. Since it regresses spontaneously, diagnosis by fine needle aspiration (FNA) cytology plays a major role in its management. We present a series of 8 cases with either FNA or biopsy diagnosis ofNF, and study the major cytological features with a review of literature on diagnostic criteria and its pitfalls. The 8 cases occurred in patients between the age of 14 to 72 years, with equal sex distribution. FNA diagnosis concurred in 4 cases. Causes of wrong diagnosis included lack of clinical information and paucicellular smear. FNA cytology is an important tool in the diagnosis of nodular fasciitis, in appropriate clinico-radiologicalsetting.


High-resolution measurements of swordfish skin surface roughness.
The three-dimensional morphology of swordfish skin roughness remains poorly understood. Subsequently, its importance to the overall physiology and hydrodynamic performance of the swordfish is yet to be determined. This is at least partly attributable to the inherent difficulty in making the required measurements of these complex biological surfaces. To address this, here two sets of novel high-resolution measurements of swordfish skin, obtained using a modular optical coherence tomography system and a gel-based stereo-profilometer, are reported and compared. Both techniques are shown to provide three-dimensional morphological data at micron-scale resolution. The results indicate that the skin surface is populated with spiny roughness elements, typically elongated in the streamwise direction, in groups of up to six, and in good agreement with previously reported information based on coarser measurements. In addition, our data also provide new information on the spatial distribution and variability of these roughness features. Two approaches, one continuous and another discrete, are used to derive various topographical metrics that characterize the surface texture of the skin. The information provided here can be used to develop statistically representative synthetic models of swordfish skin roughness.


Extended-X-ray-absorption-fine-structure investigations of zinc in 5-aminolaevulinate dehydratase.
The zinc co-ordination in 5-aminolaevulinate dehydratase (5-aminolaevulinate hydro-lyase, EC 18.104.22.168) was investigated by recording and interpreting the extended X-ray-absorption fine structure (e.x.a.f.s.) associated with the zinc K-edge. The enzyme has a molecular mass of 280 000 Da and consists of eight subunits of 35 000 Da each; the samples studied contained approx. 1 g-atom of zinc/mol of subunit. Four forms of the enzyme were investigated and details of the zinc environment were elucidated, as follows. In the native enzyme, zinc is considered to be co-ordinated to three sulphur atoms at 0.228(2)nm [2.28(2)A] and a lower-Z atom at 0.192(5)nm [1.92(5)A] (if nitrogen) or 0.189(5)nm [1.89(5)A] (if oxygen). Reaction of the enzyme with the inhibitor 2-bromo-3-(imidazol-5-yl)propionic acid produced significant changes in the e.x.a.f.s., the nature of which are consistent with co-ordination by about three sulphur atoms at 0.222(2)nm [2.22(2)A], a nitrogen atom at 0.193(5)nm [1.93(5)A] and a nitrogen atom from the inhibitor at 0.214(5)nm [2.14(5)A]. Inactivation of the enzyme by air-oxidation of essential thiol groups and binding of the substrate produce slight changes in the e.x.a.f.s. consistent with slight re-arrangement of ligands with additional lighter ligands (nitrogen or oxygen). These results, when combined with previous findings, are taken to indicate that zinc has a structural rather than a direct catalytic role in 5-aminolaevulinate dehydratase.


Breastfeeding and maternal sensitivity predict early infant temperament.
Research findings are inconclusive when it comes to whether breastfeeding is associated with the mother-infant relationship or infant temperament. We examined the association between breastfeeding at three months postpartum and infant temperament at 18 months postpartum and whether this link was affected by the mothers' anxiety and mediated by her sensitivity. We assessed 170 mothers for breastfeeding and anxiety using the Spielberger State-Trait Anxiety Inventory (STAI) at three months postpartum, maternal sensitivity using the Ainsworth Sensitivity Scale at six months postpartum and infant temperament using the Early Childhood Behaviour Questionnaire at 18 months postpartum. Mothers who breastfed at three months postpartum were more sensitive in their interactions with their infants at six months postpartum, and elevated sensitivity, in turn, predicted reduced levels of negative affectivity in infant temperament at 18 months postpartum. This indirect mediation persisted after controlling for confounders (effect ab = -0.0312 [0.0208], 95% CI = -0.0884 to -0.0031). A subsequent analysis showed that the mediation through sensitivity only occurred in women experiencing higher anxiety, with a STAI score ≥33.56 at three months (ab = -0.0250 [0.0179], 95% CI = -0.0759 to -0.0013). Our results suggest that breastfeeding and maternal sensitivity may have a positive impact on the early development of infant temperament.


PRMT5 is required for cell-cycle progression and p53 tumor suppressor function.
Protein arginine methyltransferases (PRMTs) mediate the transfer of methyl groups to arginines in proteins involved in signal transduction, transcriptional regulation and RNA processing. Tumor suppressor p53 coordinates crucial cellular processes, including cell-cycle arrest and DNA repair, in response to stress signals. Post-translational modifications and interactions with co-factors are important to regulate p53 transcriptional activity. To explore whether PRMTs modulate p53 function, we generated multiple cell lines in which PRMT1, CARM1 and PRMT5 are inducibly knocked down. Here, we showed that PRMT5, but not PRMT1 or CARM1, is essential for cell proliferation and PRMT5 deficiency triggers cell-cycle arrest in G1. In addition, PRMT5 is required for p53 expression and induction of p53 targets MDM2 and p21 upon DNA damage. Importantly, we established that PRMT5 knockdown prevents p53 protein synthesis. Furthermore, we found that PRMT5 regulates the expression of translation initiation factor eIF4E and growth suppression mediated upon PRMT5 knockdown is independent of p53 but is dependent on eIF4E. Taken together, we uncovered that arginine methyltransferase PRMT5 is a major pro-survival factor regulating eIF4E expression and p53 translation.


Risk for Clostridium difficile Infection After Allogeneic Hematopoietic Cell Transplant Remains Elevated in the Postengraftment Period.
Clostridium difficile infection (CDI) is a frequent cause of diarrhea among allogeneic hematopoietic cell transplant (HCT) recipients. It is unknown whether risk factors for CDI vary by time posttransplant. We performed a 3-year prospective cohort study of CDI in allogeneic HCT recipients. Participants were enrolled during their transplant hospitalizations. Clinical assessments were performed weekly during hospitalizations and for 12 weeks posttransplant, and monthly for 30 months thereafter. Data were collected through patient interviews and chart review, and included CDI diagnosis, demographics, transplant characteristics, medications, infections, and outcomes. CDI cases were included if they occurred within 1 year of HCT and were stratified by time from transplant. Multivariable logistic regression was used to determine risk factors for CDI. One hundred eighty-seven allogeneic HCT recipients were enrolled, including 63 (34%) patients who developed CDI. 38 (60%) CDI cases occurred during the preengraftment period (days 0-30 post-HCT) and 25 (40%) postengraftment (day >30). Lack of any preexisting comorbid disease was significantly associated with lower risk of CDI preengraftment (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.9). Relapsed underlying disease (OR, 6.7; 95% CI, 1.3-33.1), receipt of any high-risk antimicrobials (OR, 11.8; 95% CI, 2.9-47.8), and graft-versus-host disease (OR, 7.8; 95% CI, 2.0-30.2) were significant independent risk factors for CDI postengraftment. A large portion of CDI cases occurred during the postengraftment period in allogeneic HCT recipients, suggesting that surveillance for CDI should continue beyond the transplant hospitalization and preengraftment period. Patients with continued high underlying severity of illness were at increased risk of CDI postengraftment.


Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery.
Two orthogonal approaches for hit identification in drug discovery are large-scale in vitro and in silico screening. In recent years, due to the emergence of new targets and a rapid increase in the size of the readily synthesizable chemical space, there is a growing emphasis on the integration of the two techniques to improve the hit finding efficiency. Here, we highlight three examples of drug discovery projects at Merck & Co., Inc., Kenilworth, NJ, USA in which different virtual screening (VS) techniques, each specifically tailored to leverage knowledge available for the target, were utilized to augment the selection of high-quality chemical matter for in vitro assays and to enhance the diversity and tractability of hits. Central to success is a fully integrated workflow combining in silico and experimental expertise at every stage of the hit identification process. We advocate that workflows encompassing VS as part of an integrated hit finding plan should be widely adopted to accelerate hit identification and foster cross-functional collaborations in modern drug discovery.


Benefit-Cost Analysis of the Danish Sun Safety Campaign 2007-2015: Cost Savings from Sunburn and Sunbed Use Reduction and Derived Skin Cancer Reductions 2007-2040 in the Danish Population.
Ninety percent of skin cancers are avoidable. In Denmark, 16,500 cases of melanoma and keratinocyte cancers were registered in 2015. The Danish Sun Safety Campaign has campaigned since 2007, targeting overexposure to ultraviolet radiation. During 2007-2015, the key indicators of skin cancer, i.e. sunbed use and sunburn, showed annual reductions of 6% and 1%, respectively. We aimed to examine the financial savings to society as a result of the campaign reductions in skin cancer cases (2007-2040), and to examine the campaign's cost-benefit and return on investment (ROI). The analysis is based on existing data: (1) annual population-based surveys regarding the Danish population's behavior in the sun; (2) skin cancer projections; (3) relative risks of skin cancers from sunburn and sunbed use and (4) historical cancer incidences, combined with new data; (5) benefits from the avoided costs of skin cancer reductions; and (6) the costs of the Danish Sun Safety Campaign. The results were based on a reduction of 9000 skin cancer cases, saving €29 million of which €13 million were derived from sunburn reductions and €16 million from reductions in sunbed use. The ROI was €2.18. Skin cancer prevention in Denmark is cost effective. Every Euro spent by the Danish Sun Safety Campaign saved the Danish health budget €2.18 in health expenses.


Perinatal outcome in the absence of antepartum fetal heart rate acceleration.
The perinatal outcome of 27 pregnancies in which antepartum fetal activity testing revealed fetal heart rate acceleration to be either absent or less than 10 beats per minute for 80 minutes is presented. At delivery, each pregnancy was found to have one or more features consistent with uteroplacental insufficiency. These included fetal growth retardation (74%), oligohydramnios (81%), fetal acidosis (41%), meconium (30%), and placental infarction (93%). There were four fetal and seven neonatal deaths, for a perinatal mortality of 41%. Despite delivery of all live-born infants by cesarean section without labor, the infants who died during the neonatal period appeared to be in such poor condition as to preclude survival. The authors conclude that the inability of the fetus to accelerate its heart rate, when not due to maternal medications, is an ominous signal. Throughout the literature on fetal activity testing there are indications that other investigators have had similar experiences. The purpose of the present report is to direct attention to an abnormal fetal activity test result of which the significance is not widely recognized.


Absolute determination of cardiac output in intra-aortic balloon pumped patients using the radial arterial pressure trace.
We describe a new method for the absolute determination of cardiac output in intra-aortic balloon pumped (IABP) patients. The method uses the known pumping volume of the IABP balloon and the radial arterial pressure trace, which is commonly used to monitor IABP patients, to determine the cardiac output. Two pressure excursions denoted by P1-P0 and P2-P0, characterizing IABP balloon deflation, and ventricular ejection, respectively, are extracted from the radial trace. The cardiac output (CO) is then determined by the simple relation: CO = (BV) x (P2-P0)/(P1-P0) x HR where HR is the heart rate, and the value for pumped balloon volume (BV) is corrected for the effect of the pressure in the patient's aorta. Comparison with dye dilution and thermal dilution procedures as carried out on a routine basis in a clinical setting produced a good correlation (r = .928). When fit to a straight line through zero output, the data yielded a constant of proportionality of 0.973 between the above formula and the clinical procedures. The procedure does not disturb the patient in any way, and enables continuous monitoring of cardiac output. This has been implemented using a real-time, miniaturized computer and allows much more information to be obtained than in usual single measurements.


[Clinical and prognostic significance of late ventricular potentials in patients with hypertrophic cardiomyopathy].
Evaluation of clinical and prognostic value of late ventricular potentials (LVP) in patients with hypertrophic cardiomyopathy (HCMP) regarding the arrhythmic and structural-functional characteristics. 60 HCMP patients were studied: 16, 32 and 12 with apparent, latent and absent obstruction of left ventricular outflow tract. Among other clinical tests, the patients underwent echocardiography with dopplerography and Holter 24-h monitoring. LVP were registered at signal-averaged electrocardiography. The results were defined as abnormal in the presence of at least 2 of 3 standard LVP criteria: FORS > 114 ms, LAS > 38 ms, RMS 40 < 20 microV. LVP occurred in 9(15.0%) patients. All of them had obstructive HCMP (3 cases of definite and 6 cases of latent HCMP). The absence of LVP proved to be a favorable prognostic factor indicating weak probability of development of electric myocardial unstability, syncopal states and sudden death of arrhythmic genesis. The occurrence of LVP in HCMP is not closely related to structural-functional condition of the heart. Detection of LVP is not a reliable predictor of sudden arrhythmic death risk.


Combining hidden Markov models for comparing the dynamics of multiple sleep electroencephalograms.
In this manuscript, we consider methods for the analysis of populations of electroencephalogram signals during sleep for the study of sleep disorders using hidden Markov models (HMMs). Notably, we propose an easily implemented method for simultaneously modeling multiple time series that involve large amounts of data. We apply these methods to study sleep-disordered breathing (SDB) in the Sleep Heart Health Study (SHHS), a landmark study of SDB and cardiovascular consequences. We use the entire, longitudinally collected, SHHS cohort to develop HMM population parameters, which we then apply to obtain subject-specific Markovian predictions. From these predictions, we create several indices of interest, such as transition frequencies between latent states. Our HMM analysis of electroencephalogram signals uncovers interesting findings regarding differences in brain activity during sleep between those with and without SDB. These findings include stability of the percent time spent in HMM latent states across matched diseased and non-diseased groups and differences in the rate of transitioning.


Quantum model of light transmission in array waveguide gratings.
We develop, to the best of our knowledge, the first model for an array waveguide grating (AWG) device subject to quantum inputs and analyze its basic transformation functionalities for single-photon states. A commercial, cyclic AWG is experimentally characterized with weak input coherent states as a means of exploring its behaviour under realistic quantum detection. In particular it is shown the existence of a cutoff value of the average photon number below which quantum crosstalk between AWG ports is negligible with respect to dark counts. These results can be useful when considering the application of AWG devices to integrated quantum photonic systems.


[An experimental study on the effects of the chronic administration of an angiotensin converting enzyme inhibitor (captopril) on blood pressure and the renin-angiotensin-aldosterone system (author's transl)].
The chronic effects of the oral administration of an angiotensin converting enzyme inhibitor (captopril, 63-80 mg/kg/day) on blood pressure and the renin-angiotensin-aldosterone system were studied in normotensive male Wistar rats. The blood pressure (BP), plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate concentration (PRS), plasma aldosterone concentration (PAC), and renal renin content (RRC) were measured 2, 9, 19, 29 and 58 days after the administration of the agent. Blood pressure was determined in unanesthetized rats, and blood samples were obtained by decapitation. Furthermore, blood pressure responses to bolus injections of angiotensin II (AII, 80 ng/kg), angiotensin I (AI, 80 ng/kg) and bradykinin (BK, 10 micrograms/kg) were examined in unanesthetized rats which had been given the agent for 20 days. The BP of the rats which had been given captopril for 9 days or more was significantly lower than in the control rats. The reduction in heart weight in the captopril rats reached a statistically significant level 58 days after the administration of the agent. The PRA and the PRC markedly increased, and the PRS and the PAC both decreased in the captopril rats. The RRC which was reduced after 2 days of captopril administration markedly increased thereafter. In the captopril rats, significant negative correlations were observed between PRC and PRS (r=-0.43, p<0.01), and between BP and PRC (r=-0.60, p<0.001). The PRC significantly correlated with the RRC in the control rats (r=-0.44, p<0.01) while such a relationship did not exist in the captopril rats. Although the pressor responses to AII were similar in the captopril and the control rats, the responses to AI were reduced to 50% of the responses to AII in the captopril rats. The blood pressure reduction in response to BK in the captopril rats was 2.3 times as great as that in the control rats. Thus, it is suggested that the increases in PRA, PRC and RRC in the captopril rats may be related to both the blood pressure reduction and interruption of the negative feedback inhibition of renin synthesis and release by AII, and that the decrease in PRS in the captopril rats is due to the increased consumption and probably to the decreased rate of substrate production in the liver which is secondary to the decrease in plasma AII. The lack of significant positive correlation between PRC and RRC in the captopril rats seems to demonstrate that captopril may modify the relationship between them. The results also show that the chronic administration of captopril lowers blood pressure in normotensive animals. The blood pressure reduction by captopril may be related to the decreased kininase activity which is suggested by the enhanced depressor responses to BK, as well as the lowered plasma level of AII.


Clinicopathological characteristics predicting advanced stage and surgical margin invasion of oral squamous cell carcinoma: A single-center study on 10 years of cancer registry data.
The incidence profile of oral squamous cell carcinoma (OSCC) has not previously been comprehensively reported in Indonesia. The present study aimed to identify clinicopathological characteristics of patients with OSCC according to sex and age, to analyze histological differentiation patterns specific to tumor subsites, to highlight the role of lymphovascular invasion (LVI) in metastasis, and to develop a model to predict advanced stage and margin invasion. A retrospective cross-sectional study was performed using 581 medical records and pathological specimens from cancer registry data in the Dr Cipto Mangunkusumo Hospital (Jakarta, Indonesia), between January 2011 and December 2020. Clinicopathological characteristics were analyzed using parametric and non-parametric tests. Multivariate logistic regression analyses were performed for eligible parameters, identified using bivariate analysis, to predict advanced stage and margin invasion. Calibration of the prediction model was evaluated using the Hosmer-Lemeshow test, its discrimination value assessed using the receiver operating characteristic and area under the receiver operating characteristic curve (AUC). Sex-specific patterns in tumor subsites and differences in clinical staging according to age were demonstrated in the patients with OSCC. The proportion of well-differentiated cases was significantly higher in most tumor subsites, except in the buccal mucosa (more moderately differentiated cases) and floor of the mouth (well and moderately differentiated cases being equal). LVI was significantly associated with nodal metastasis but not distant metastasis. Multivariate analysis demonstrated that age ≤45 years [odds ratio (OR), 2.26] and LVI (OR, 8.42) predicted patients having advanced-stage OSCC among general populations (AUC, 0.773); however, LVI (OR, 8.28) was the sole predictor of advanced stage amongst young patients (AUC, 0.737). Margin invasion was predicted solely by tumor subsite, including mouth not otherwise specified (OR, 3.04) and palate (OR, 6.13), in the general population (AUC, 0.711). Furthermore, margin invasion was predicted by the palate subsite (OR, 38.77) and LVI (OR, 11.61) in young patients (AUC, 0.762). Investigating young patients thoroughly when finding SCC in the mouth and palate, and assessing LVI, especially among young patients, is critical to prevent advanced staging and margin invasion.


Length of Stay and Cost of Pediatric Readmissions.
Readmissions burden the health care system. Despite increasing attention to readmission rates, little is known about the duration and cost of readmissions. The objective of this study was to assess, nationally, the length of stay (LOS) and costs for 30-day readmissions in children. We performed a retrospective analysis of 30-day readmissions by using the 2013 Nationwide Readmissions Database. We used generalized linear mixed effects models adjusted for important clinical and demographic factors to assess LOS and cost for index admissions, readmissions, and the episode of care (index admission plus readmission). A total of 125 183 (4.5%) children had a 30-day readmission; 87.1% of readmissions were to the same hospital. Readmitted children had an adjusted episode LOS that was 2 times longer (5.8 vs 2.9 days) and total costs that were 2.3 times higher ($12 250 vs $5340) than those who were not readmitted. Associations of readmissions with episode LOS and costs varied significantly by condition (P < .001). Children readmitted to a different versus the same hospital had an episode LOS that was the same (5.8 days; P = .279) but higher episode of care costs ($15 876 vs $11 661; P < .001). Readmitted children spend twice as many days in the hospital compared with children who are not readmitted and have higher hospital costs, especially when readmitted to a different hospital. In addition to readmission rate, readmission metrics may benefit from measurement of total LOS and costs for both the index admission and its associated readmission.


Dying cancer patients' own opinions on euthanasia: an expression of autonomy? A qualitative study.
Deliberations on euthanasia are mostly theoretical, and often lack first-hand perspectives of the affected persons. Sixty-six patients suffering from cancer in a palliative phase were interviewed about their perspectives of euthanasia in relation to autonomy. The interviews were transcribed verbatim and analysed using qualitative content analysis with no predetermined categories. The informants expressed different positions on euthanasia, ranging from support to opposition, but the majority were undecided due to the complexity of the problem. The informants' perspectives on euthanasia in relation to autonomy focused on decision making, being affected by (1) power and (2) trust. Legalization of euthanasia was perceived as either (a) increasing patient autonomy by patient empowerment, or (b) decreasing patient autonomy by increasing the medical power of the health care staff, which could be frightening. The informants experienced dependence on others, and expressed various levels of trust in others' intentions, ranging from full trust to complete mistrust. Dying cancer patients perceive that they cannot feel completely independent, which affects true autonomous decision making. Further, when considering legalization of euthanasia, the perspectives of patients fearing the effects of legalization should also be taken into account, not only those of patients opting for it.


Genetic variants in genes of the inflammatory response in association with infective endocarditis.
Inflammation in infective endocarditis (IE) is a complex network including interactions of inflammatory cytokines and other components of host response. Certainly, any variation in this network could influence susceptibility or disease progression of IE. In this study, 14 single nucleotide variants (SNVs) in genes coding for interleukin-1β, interleukin-6, interleukin-10, toll-like receptor-4, tumor necrosis factor-α, selectin E and intercellular adhesion molecule-1 were analyzed for an association with susceptibility to IE and correlated with disease-related laboratory parameters. Furthermore, the occurrence of SNVs was examined to elucidate pathogen-dependent associations. The distribution of SNVs was determined in IE-patients and healthy blood donors by RFLP analysis. White blood cells (WBC) were counted using flow cytometry, concentration of C-reactive protein and procalcitonin was measured immunologically. Interleukin-6 c.471+870G>A genotypes differed significantly between IE patients and controls. The frequency of the heterozygote genotype GA was considerably higher in the patient group (68.9% vs. 43.8%, Pc<0.0003). Interleukin-6 c.-237 minor allele frequency was increased in patients, although not statistically significant. Additionally, we detected a potential relation between interleukin-1β c.315C>T and IE. Pathogen-dependent analysis showed no significantly associated subgroup in relation to IE susceptibility, but gave hints towards alterations regarding Enterococcus-caused IE cases. Patients with genotype selectin-E c.-19 GT tend to have higher preoperative WBC counts than patients with genotype GG. We further showed an association between two interleukin-1β SNVs and laboratory biomarkers. This study shows genetic predispositions for the establishment of IE. Furthermore, correlation of SNVs with disease-related biomarkers suggests a role of genetic variants regarding the inflammatory response in IE.


Open-path spectroscopic methane detection using a broadband monolithic distributed feedback-quantum cascade laser array.
Methane is a powerful greenhouse gas that has both natural and anthropogenic sources. The ability to measure methane using an integrated path length approach such as an open/long-path length sensor would be beneficial in several environments for examining anthropogenic and natural sources, including tundra landscapes, rivers, lakes, landfills, estuaries, fracking sites, pipelines, and agricultural sites. Here a broadband monolithic distributed feedback-quantum cascade laser array was utilized as the source for an open-path methane sensor. Two telescopes were utilized for the launch (laser source) and receiver (detector) in a bistatic configuration for methane sensing across a 50 m path length. Direct-absorption spectroscopy was utilized with intrapulse tuning. Ambient methane levels were detectable, and an instrument precision of 70 ppb with 100 s averaging and 90 ppb with 10 s averaging was achieved. The sensor system was designed to work "off the grid" and utilizes batteries that are rechargeable with solar panels and wind turbines.


Direct force measurements of the streptavidin-biotin interaction.
The interaction between streptavidin and its ligand, biotin, were studied by direct force measurements. The complimentary approaches of surface force apparatus (SFA) and atomic force microscopy (AFM) were used to elucidate both long-range and short-range adhesive interactions of the streptavidin biotin interaction. The high spatial resolution of the SFA provided a detailed profile of the intersurface forces of apposing surfaces functionalized with streptavidin and biotin. Measurements obtained by the SFA corresponded to long and intermediate-range forces that are important in determining ligand receptor association. AFM was used to measure the unbinding force of individual streptavidin biotin complexes. These measurements revealed the short-range interactions (i.e. hydrophobic and hydrogen bonding forces) that stabilize the intermolecular bond.


Sleep apnoea and cognitive impairment: myth or reality?
A growing number of studies in animal models have highlighted the link between sleep disorders and Alzheimer's disease (AD). In the absence of curative treatment, it is therefore important to consider any comorbidities that may influence the course of AD such as obstructive sleep apnoea-hypnoea (OSAH) and its syndrome (OSAHS), which appear to be potentially interesting because it occurs frequently, it is treatable and it is often associated with cognitive impairment. The association between OSAH/OSAHS and cognition is variable across studies, but OSAH/OSAHS is more common in older patients with AD than in cognitively normal individuals. OSAH/OSAHS is often associated with the subsequent development of mild cognitive impairment and AD. Although there is no evidence that treatment of OSAH/OSAHS in AD would have a major impact on the course of the disease, treatment would appear to improve cognition in AD patients with OSAH/OSAHS. Finally, the literature suggests a link between OSAH/OSAHS and AD biomarkers. Taken together, these data highlight the importance of detecting and treating OSAHS in this population.


The lung endothelin system: a potent therapeutic target with bosentan for the amelioration of lung alterations in a rat model of diabetes mellitus.
The aim of this study is to show the effect of a new mechanism on endothelin (ET) receptors in the physiopathology of diabetes-related pulmonary injury. We tested the hypothesis that dual ET-1 receptor antagonism via bosentan can reverse diabetes-induced lung injury. The rats (24 male) were separated into four groups: group 1 (HEALTHY): Control group; group 2 (DM): Streptozotocin 60 mg/kg (i.p.); group 3 (DM + BOS-1): Diabetes + bosentan 50 mg/kg per-os; group 4 (DM + BOS-2): Diabetes + bosentan 100 mg/kg per-os. The bosentan treatment was initiated immediately after the onset of STZ-induced diabetes and continued for 6 weeks. In the treatment group, SOD activity was significantly increased, although GSH and MDA levels and TNF-α and TGF-β gene expression were decreased. Bosentan 50 mg/kg and bosentan 100 mg/kg showed a significantly down-regulatory effect on ET-1, ET-A, and ET-B mRNA expression. In conclusion, increased endothelin levels in the lung associated with diabetes may be one cause of endothelial dysfunction, cytokine increase, and oxidant/antioxidant imbalance in the pathogenesis of complications that may develop during diabetes. With its multiple effects, bosentan therapy may be an effective option against complications that may develop in association with diabetes.


[The modulatory action of superlow doses of mediators on the functional activity of the neuronal membrane].
It was shown that acetylcholine and gamma-aminobutyric acid at extremely low concentrations, which do not activate receptor-binding ionic channels, modulate the activity of NA-K-pump and Na:Ca exchange, the intracellular level of cAMP and chemosensitivity of the neuronal membrane. These data provide a new evidence in support for Koshtoiants's enzymochemical hypothesis in which synaptic transmitters are considered to be metabolic modulators for postsynaptic neurones.


A cross-sectional survey of supports for evidence-informed decision-making in healthcare organisations: a research protocol.
This protocol builds on the development of a) a framework that identified the various supports (i.e. positions, activities, interventions) that a healthcare organisation or health system can implement for evidence-informed decision-making (EIDM) and b) a qualitative study that showed the current mix of supports that some Canadian healthcare organisations have in place and the ones that are perceived to facilitate the use of research evidence in decision-making. Based on these findings, we developed a web survey to collect cross-sectional data about the specific supports that regional health authorities and hospitals in two Canadian provinces (Ontario and Quebec) have in place to facilitate EIDM. This paper describes the methods for a cross-sectional web survey among 32 regional health authorities and 253 hospitals in the provinces of Quebec and Ontario (Canada) to collect data on the current mix of organisational supports that these organisations have in place to facilitate evidence-informed decision-making. The data will be obtained through a two-step survey design: a 10-min survey among CEOs to identify key units and individuals in regard to our objectives (step 1) and a 20-min survey among managers of the key units identified in step 1 to collect information about the activities performed by their unit regarding the acquisition, assessment, adaptation and/or dissemination of research evidence in decision-making (step 2). The study will target three types of informants: CEOs, library/documentation centre managers and all other key managers whose unit is involved in the acquisition, assessment, adaptation/packaging and/or dissemination of research evidence in decision-making. We developed an innovative data collection system to increase the likelihood that only the best-informed respondent available answers each survey question. The reporting of the results will be done using descriptive statistics of supports by organisation type and by province. This study will be the first to collect and report large-scale cross-sectional data on the current mix of supports health system organisations in the two most populous Canadian provinces have in place for evidence-informed decision-making. The study will also provide useful information to researchers on how to collect organisation-level data with reduced risk of self-reporting bias.


British military women: combat exposure, deployment and mental health.
Internationally, women are about to undertake combat duties alongside their male colleagues. The psychological effect of this policy change is largely unknown. To explore the mental health impact of combat exposure among military women. Self-report, between-subjects survey data were collected in Iraq and Afghanistan on four occasions between 2009 and 2014 (n = 4139). Differences in mental health, stigmatization, deployment experiences, intimate relationship impact, perception of family support levels, unit cohesion, leadership and help-seeking were compared between deployed men and women. Comparisons were repeated with the study sample stratified by level of combat exposure. Outcomes were examined using logistic regression adjusted for socio-demographic, mental health and military factors. Overall, 4.1% of women and 4.3% of men reported post-traumatic stress disorder (PTSD) (odds ratio (OR) 1.31, 95% confidence interval (95% CI) 0.70-2.46); 22% of women and 16% of men reported symptoms of common mental disorder (CMD) (OR 1.52, 95% CI 1.11-2.08). Women were less likely to report mental health-related stigmatization (OR 0.68, 95% CI 0.53-0.87), negative relationship impact from deployment (OR 0.69, 95% CI 0.49-0.98) and subjective unit cohesion (OR 0.69, 95% CI 0.53-0.90). Help-seeking for emotional problems was similar by gender (OR 1.22, 95% CI 0.84-1.77). Overall, outcomes were minimally impacted by level of combat exposure. Although women experienced more CMD symptoms, PTSD symptoms were similar by gender. Subject to confirmation of the study findings, women may not require enhanced mental healthcare during deployment for exposure-based conditions such as PTSD when undertaking the ground close combat role.


Possible stem cell origin of human cholangiocarcinoma.
To investigate the expression of CD34 and c-kit (receptor of stem cell factor) in cholangiocarcinoma. Fifteen cases of intrahepatic cholangiocarcinoma and 17 cases of extrahepatic cholangiocarcinoma were studied in this experiment. Using Envision detection system, paraffin-embedded sections of the resected cholangiocarcinoma tissue were stained with antibodies against CD34 and c-kit, respectively. The sections were counterstained with hematoxylin, and the results were examined under light microscope. Normal tonsil and mammary tissues were used as positive controls for CD34 and c-kit, respectively. CD34 was positive in all sections, but only in capillary endothelial cells of tumor tissue. No cholangiocarcinoma cells were positive for CD34. In one case of extrahepatic cholangiocarcinoma, a few tumor cells (about 5%) were immunoreactive with c-kit. CD34 or c-kit positive cells in liver tissue may represent liver stem cells, as they can differentiate into mature biliary cells in vitro. The expression of c-kit by some cholangiocarcinoma cells suggests that cholangiocarcinoma might originate from liver stem cells. However, other mechanisms of hepatocarcinogenesis, such as de-differentiation of mature cholangiocytes, may also exist.


[Resolubility in oral health for primary care as an instrument for the evaluation of health systems].
This study sought to evaluate which health system - either the Family Health Strategy (FHS) or the traditional model established in the Basic Health Units (BHU) - was more effective during the period between 2007 and 2009 in relation to the oral health needs of the population of the city of Marilia in the state of São Paulo. It involved a retrospective ecological study with a stratified random sample of 50% of the universe of the study area for the 12 BHU and 37% of the 29 Family Health Units (FHU) in the municipality, whereby 6 BHU and 11 FHS were randomly selected. The data collected for observation were gathered through the management reports of the SIAB and Oral Health Assessment Report information systems. Exploratory data analysis and the Student t test were performed in order to analyze the resolubility of different systems of health care. It was observed that the coefficients relating to Initial Dental Treatment were not statistically different, though with respect to the Completed Initial Treatment coefficient for the population greater than two years the values were 16.74 for the FHS model and 6.93 for the BHU model, with a statistically significant difference of 40.97% resolubility for the BHU in relation to 83.56% for the FHS (p < 0.05).


In-depth characterization of the placental imprintome reveals novel differentially methylated regions across birth weight categories.
Imprinted genes play a pivotal role in placental processes underlying fetal development, and much interest centers on discerning whether these loci, via changes in DNA methylation and/or gene expression, inform disruptions in appropriate fetal growth. In this study, we comprehensively profiled DNA methylation across the placental imprintome and assessed the relationship with gene expression levels and aberrant fetal growth.Placental DNA methylation across 153 imprinted loci, including imprint control regions (ICR) and surrounding non-ICR regions, was surveyed using the Nimblegen TruSeq bisulfite sequencing platform among participants enrolled in the Rhode Island Child Health Study (RICHS, n = 163). Methylation and gene expression associations were assessed using eQTM analysis. Differential methylation analysis contrasting small (SGA) and large for gestational age (LGA) infants against appropriate for gestational age (AGA) infants was assessed using the DMRcate R package.We identified 34 SGA-related differentially methylated regions (DMRs) and 9 LGA-related DMRs (FDR<0.05), and these BW-DMRs predominated in promoter and intronic regions. We observed overall hypomethylation among SGA-DMRs overlapping maternally expressed (paternally imprinted) genes while no parent-of-origin effect was observed among LGA DMRs. Three BW-DMRs, mapping to GABRG3, IGF1R and MEST, were common to SGA and LGA placenta. We did not observe significant correlations between BW-DMR-associated CpG methylation and gene expression levels.We report the first in-depth characterization of the placental imprintome in a population-wide setting. Our findings reveal growth-related differences in methylation without concomitant expression differences in regions that extend beyond typically interrogated imprinted loci, highlighting potentially novel placental biomarkers of growth and development.


Blind Universal Bayesian Image Denoising with Gaussian Noise Level Learning.
Blind and universal image denoising consists of using a unique model that denoises images with any level of noise. It is especially practical as noise levels do not need to be known when the model is developed or at test time. We propose a theoretically-grounded blind and universal deep learning image denoiser for additive Gaussian noise removal. Our network is based on an optimal denoising solution, which we call fusion denoising. It is derived theoretically with a Gaussian image prior assumption. Synthetic experiments show our network's generalization strength to unseen additive noise levels. We also adapt the fusion denoising network architecture for image denoising on real images. Our approach improves real-world grayscale additive image denoising PSNR results for training noise levels and further on noise levels not seen during training. It also improves state-of-the-art color image denoising performance on every single noise level, by an average of 0.1dB, whether trained on or not.


Music in palliative care: a qualitative study with patients suffering from cancer.
The palliative care unit is an emotionally challenging place where patients and their families may feel at loss. Art can allow the expression of complex feelings. We aimed to examine how cancer patients hospitalized in the palliative care unit experienced a musical intervention. We conducted a qualitative study based on semi-structured interviews. The study took place in a palliative care unit from 18 January 2017 to 17 May 2017. Two artists performed in the palliative care unit once a week from 9:30 am to 5:30 pm. The data from patient interviews were analysed based on an inductive approach to the verbatim accounts. The accounts we gathered led us to weigh the positive emotions engendered by this musical intervention against the potential difficulties encountered. The artists opened a parenthesis in the care process and brought joy and well-being to the palliative care unit. Patients also encountered difficulties during the intervention: reference to an altered general state, to loss of autonomy; a sense of the effort required, of fatigue; an adaptation period; reference to the end of life, to death; a difficulty in choosing songs. Although music appeared to benefit the patients, it sometimes reminded them of their altered state. The difficulties experienced by patients during the experience were also related to physical exhaustion. Additional studies are needed to determine the benefits of music for patients and their families in the palliative care unit.


Disulfide bonding controls the processing of retroviral envelope glycoproteins.
The mitogenic membrane glycoprotein (gp55) encoded by Friend erythroleukemia virus is inefficiently processed from the rough endoplasmic reticulum (RER) and only 3-5% reaches plasma membranes. Because this processed component (gp55P) contains larger and more complex oligosaccharides, it can be separated from RER gp55. In nonreducing conditions, gp55P is a unique disulfide-bonded dimer, whereas RER gp55 consists of monomers and dimers with diverse intrachain and interchain disulfide bonds. This suggests that gp55 folds heterogeneously and that only one homodimer is competent for export from the RER. Pulse-chase analyses of gp55 components labeled with radioactive amino acids indicated that formation of diverse disulfide-bonded components occurred within minutes of polypeptide synthesis and that malfolded components did not later isomerize to generate dimers competent for export from the RER. Chemical studies suggested that all 12 cysteines of gp55 were oxidized within 5 min after synthesis of the protein. In contrast, the envelope glycoprotein precursor (gPr90) encoded by a replication-competent murine leukemia virus folds more homogeneously, and it is then processed and cleaved to form an extracellular glycoprotein gp70 plus a transmembrane protein p15E. The fully processed glycoprotein contains an unoxidized cysteine sulfhydryl that isomerizes reversibly with a disulfide bond that links gp70 to p15E. Consequently, only a proportion of gp70 and p15E is disulfide-bonded, and dissociation occurs when the environment becomes even slightly reducing. The gp55 glycoprotein appears to be an extreme example of protein malfolding associated with imprecise and irreversible disulfide bonding. We discuss evidence that folding inefficiencies are common for retroviral proteins that have newly evolving pathogenic functions.


Determinants of capacious memory: a process-dissociation and experiential approach.
The aim of this study is to delineate some important circumstances where exceptionally good memory performance, or capacious memory occurs. A further aim is to study memory processes involved in this memory phenomenon. In a first experiment, participants looked through two series of pictures differing in number and were evaluated in two-alternative forced-choice and yes-no recognition memory tasks combined in a process-dissociation procedure. Moreover, participants were asked to provide remember and know responses to tap recollective experience. The results as to forced-choice recognition task accuracy and according to process-dissociation procedure estimates were replicated in a second experiment with a more intrinsic contextual manipulation, and in a third, forgetting experiment. In addition to replicating previous findings, the results show (a) that capacious memory is associated with strong feelings of recollection; and (b) that familiarity (in terms of the process-dissociation framework) contributes to this phenomenon.


A comparison of outpatient healthcare expenditures between public and private medical institutions in urban China: an instrumental variable approach.
The growth of healthcare expenditure provokes constant comments and discussions, as countries battle the issues on cost containment and cost effectiveness. Prior to 1978, medical institutions in China were either state-owned or were collective public hospitals. Since 1978, China has been trying to rebuild its healthcare system, which was destroyed during the 'cultural revolution', allowing private medical institutions to deliver healthcare services. As a result, private medical institutions have grown from 0% to 28.57% between 1978 and 2010. In this context, we compare outpatient healthcare expenditures between public and private medical institutions. The central problem of this comparison is that the choice of medical institution is endogenous. So we apply an instrumental variable (IV) framework utilizing geographic information (whether the closest medical institution is private) as the instrument while controlling for severity of health and other relevant confounding factors. Using China's Urban Resident Basic Medical Insurance Survey 2008-2010, we found that there is no difference in expenditure between public and private medical institutions when IV framework is used. Our econometric tests suggest that our IV model is specified appropriately. However, the ordinary least square model, which is inconsistent in the presence of endogenous regressor(s), reveals that public medical institutions are more expensive.


Toward an understanding of disengagement from HIV treatment and care in sub-Saharan Africa: a qualitative study.
The rollout of antiretroviral therapy in sub-Saharan Africa has brought lifesaving treatment to millions of HIV-infected individuals. Treatment is lifelong, however, and to continue to benefit, patients must remain in care. Despite this, systematic investigations of retention have repeatedly documented high rates of loss to follow-up from HIV treatment programs. This paper introduces an explanation for missed clinic visits and subsequent disengagement among patients enrolled in HIV treatment and care programs in Africa. Eight-hundred-ninety patients enrolled in HIV treatment programs in Jos, Nigeria; Dar es Salaam, Tanzania; and Mbarara, Uganda who had extended absences from care were tracked for qualitative research interviews. Two-hundred-eighty-seven were located, and 91 took part in the study. Interview data were inductively analyzed to identify reasons for missed visits and to assemble them into a broader explanation of how missed visits may develop into disengagement. Findings reveal unintentional and intentional reasons for missing, along with reluctance to return to care following an absence. Disengagement is interpreted as a process through which missed visits and ensuing reluctance to return over time erode patients' subjective sense of connectedness to care. Missed visits are inevitable over a lifelong course of HIV care. Efforts to prevent missed clinic visits combined with moves to minimize barriers to re-entry into care are more likely than either approach alone to keep missed visits from turning into long-term disengagement.


[Profile of the brazilian nursing student].
Because the Author believes in the importance of keeping up to date information on demographic data, socio-economical origin, curriculum, present economic situation, request for scholar development, aspiration and information about carer expectation, that caracterize nursing students, and may furnish elements to improve programs and methods of clinical practice, this research was performed in 1976 withe the sole objetive of obtaining these data. It is a descriptive - type of study and the data were collected through the application of a 39 - item - questionnaire applied to 150 (1973) and 300 (1976) third grade students of Nursing Schools of the State of São Paulo. Therefore the student profile that was obtained through this research shows emergency of correlated problems, that interfere directly on scholar efficiency. Trying to solve them within our nursing teaching boudaires seems to be more realistic. The way to try solving them requires from nursing educators efforts in order to search for and determine more adequate teaching methods and techniques. This task is of the utmost urgency in one has in mind the need of promoting efforts to increase students profits and a result of it, more efficient professionals in the future.


Simple detection of the 5S ribosomal RNA of Pneumocystis carinii using in situ hybridisation.
To investigate the effectiveness of digoxigenin incorporated double stranded DNA probes produced by the polymerase chain reaction (PCR), for the detection of Pneumocystis carinii, using in situ hybridisation (ISH). Formalin fixed, paraffin wax embedded sections of 26 human lung samples from 11 patients with P carinii pneumonia (PCP), and 15 with various types of fungal and viral pneumonia, were obtained during necropsy or transbronchial lung biopsy. Three additional PCP induced rat lung samples were also tested. PCR probes were prepared using the digoxigenin labelling mixture, and they were amplified from the DNA of a PCP induced rat lung after administration of dexamethasone, on the basis that 5S ribosomal RNA sequences are identical in human and rat P carinii. ISH was performed using this probe, and visualised using the digoxigenin nucleic acid detection kit. An immunohistochemical study using anti-human Pneumocystis monoclonal antibody was also carried out in parallel. ISH positively stained eight (of eight) lung necropsy specimens from patients with PCP, three (of three) transbronchial lung biopsy specimens from patients with PCP, and none of the three PCP induced rat lung specimens. In contrast, none of the specimens from patients with pneumonia caused by Aspergillus sp (n = 5), Candida sp (n = 4), Cryptococcus sp (n = 2), mucormycosis (n = 2), or cytomegalovirus (n = 2) were positive on ISH or immunohistochemistry. Using a digoxigenin labelled PCR probe for the entire 5S rRNA sequence in conjunction with conventional staining, ISH is highly reactive and specific for the diagnosis of PCP.


Analysis of titanium pigments in human lung tissue.
Methods are described for the unequivocal identification of mineral deposits in lung tissues obtained during the autopsy of a titanium dioxide-exposed worker who died of an undifferentiated malignant tumor. The methods included scanning and transmission electron microscopy, electron and X-ray diffractometry, and atomic absorption spectroscopy. The presence of considerable amounts of rutile was revealed. Despite this heavy loading, no lung tissue reaction was evident. Within the limits imposed by the period since the first exposure (6 years), this finding lends support to the supposition that the rutile crystal modification of titanium dioxide is biologically inert.


Pollution Weather Prediction System: Smart Outdoor Pollution Monitoring and Prediction for Healthy Breathing and Living.
Air pollution has been a looming issue of the 21st century that has also significantly impacted the surrounding environment and societal health. Recently, previous studies have conducted extensive research on air pollution and air quality monitoring. Despite this, the fields of air pollution and air quality monitoring remain plagued with unsolved problems. In this study, the Pollution Weather Prediction System (PWP) is proposed to perform air pollution prediction for outdoor sites for various pollution parameters. In the presented research work, we introduced a PWP system configured with pollution-sensing units, such as SDS021, MQ07-CO, NO2-B43F, and Aeroqual Ozone (O3). These sensing units were utilized to collect and measure various pollutant levels, such as PM2.5, PM10, CO, NO2, and O3, for 90 days at Symbiosis International University, Pune, Maharashtra, India. The data collection was carried out between the duration of December 2019 to February 2020 during the winter. The investigation results validate the success of the presented PWP system. In the conducted experiments, linear regression and artificial neural network (ANN)-based AQI (air quality index) predictions were performed. Furthermore, the presented study also found that the customized linear regression methodology outperformed other machine-learning methods, such as linear, ridge, Lasso, Bayes, Huber, Lars, Lasso-lars, stochastic gradient descent (SGD), and ElasticNet regression methodologies, and the customized ANN regression methodology used in the conducted experiments. The overall AQI values of the air pollutants were calculated based on the summation of the AQI values of all the presented air pollutants. In the end, the web and mobile interfaces were developed to display air pollution prediction values of a variety of air pollutants.


Influence of crossbridge compliance on the force-velocity relation of muscle.
It is shown that muscle models which describe force generation as being dependent on the extension of the individual crossbridges produce a force-velocity relation of the form: Vf= Visotonic--1/KHS dP/dt. The derivation of this equation is independent of the details of activation and the kinetics of the crossbridges. The velocity, Vf, represents the relative filament velocity, and Visontonic is the relative filament velocity which would maintain a constant muscle force. P. The quantity KHS is the net stiffness of all the force-generating crossbridges in one-half a sarcomere. Experimental methods for determining KHS are suggested . To study the force-velocity relation, computer simulations based on A. F.Huxley's 1957 kinetic model were conducted for isometric and isotonic twitch contractions. The relative filament velocity is found to depend on the contraction mode, exhibiting a sudden increase in an isometric-to-isontonic changeover and a decrease in the reverse process.


Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer.
Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10-3.39), rs5275 (HR:1.58, 95% CI:1.09-2.27), and rs689470 (HR:3.38, 95% CI:1.09-10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31-0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14-7.63 and HR:3.23, 95% CI:1.03-10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events.


MRI-determined left ventricular "crescent effect": a consequence of the slight deviation of contents of the pericardial sack from the constant-volume state.
During one cardiac cycle, the volume encompassed by the pericardial sack in healthy subjects remains nearly constant, with a transient +/-5% decrease in volume at end systole. This "constant-volume" attribute defines a constraint that the longitudinal versus radial pericardial contour dimension relationship must obey. Using cardiac MRI, we determined the extent to which the constant-volume attribute is valid from four-chamber slices (two-dimensional) compared with three-dimensional volumetric data. We also compared the relative percentage of longitudinal versus radial (short-axis) change in cross-sectional area (dimension) of the pericardial contour, thereby assessing the fate of the +/-5% end-systolic volume decrease. We analyzed images from 10 normal volunteers and 1 subject with congenital absence of the pericardium, obtained using a 1.5-T MR scanner. Short-axis cine loop stacks covering the entire heart were acquired, as were single four-chamber cine loops. In the short-axis and four-chamber slices, relative to midventricular end-diastolic location, end-systolic pericardial (left ventricular epicardial) displacement was observed to be radial and maximized at end systole. Longitudinal (apex to mediastinum) pericardial contour dimension change and pericardial area change on the four-chamber slice were negligible throughout the cardiac cycle. We conclude that the +/-5% end-systolic decrease in the volume encompassed by the pericardial sack is primarily accounted for by a "crescent effect" on short-axis views, manifesting as a nonisotropic radial diminution of the pericardial/epicardial contour of the left ventricle. This systolic drop in cardiac volume occurs primarily at the ventricular level and is made up during the subsequent diastole when blood crosses the pericardium in the pulmonary venous Doppler D wave during early rapid left ventricular filling.


Coronary Computed Tomography Angiography vs Functional Stress Testing for Patients With Suspected Coronary Artery Disease: A Systematic Review and Meta-analysis.
Coronary computed tomography angiography (CCTA) is a new approach for the diagnosis of anatomical coronary artery disease (CAD), but it is unclear how CCTA performs compared with the standard approach of functional stress testing. To compare the clinical effectiveness of CCTA with that of functional stress testing for patients with suspected CAD. A systematic literature search was conducted in PubMed and MEDLINE for English-language randomized clinical trials of CCTA published from January 1, 2000, to July 10, 2016. Researchers selected randomized clinical trials that compared a primary strategy of CCTA with that of functional stress testing for patients with suspected CAD and reported data on patient clinical events and changes in therapy. Two reviewers independently extracted data from and assessed the quality of the trials. This analysis followed the PRISMA statement for reporting systematic reviews and meta-analyses and used the Cochrane Collaboration's tool for assessing risk of bias in randomized trials. The Mantel-Haenszel method was used to conduct the primary analysis. Summary relative risks were calculated with a random-effects model. The outcomes of interest were all-cause mortality, cardiac hospitalization, myocardial infarction, invasive coronary angiography, coronary revascularization, new CAD diagnoses, and change in prescription for aspirin and statins. Thirteen trials were included, with 10 315 patients in the CCTA arm and 9777 patients in the functional stress testing arm who were followed up for a mean duration of 18 months. There were no statistically significant differences between CCTA and functional stress testing in death (1.0% vs 1.1%; risk ratio [RR], 0.93; 95% CI, 0.71-1.21) or cardiac hospitalization (2.7% vs 2.7%; RR, 0.98; 95% CI, 0.79-1.21), but CCTA was associated with a reduction in the incidence of myocardial infarction (0.7% vs 1.1%; RR, 0.71; 95% CI, 0.53-0.96). Patients undergoing CCTA were significantly more likely to undergo invasive coronary angiography (11.7% vs 9.1%; RR, 1.33; 95% CI, 1.12-1.59) and revascularization (7.2% vs 4.5%; RR, 1.86; 95% CI, 1.43-2.43). They were also more likely to receive a diagnosis of new CAD and to have initiated aspirin or statin therapy. Compared with functional stress testing, CCTA is associated with a reduced incidence of myocardial infarction but an increased incidence of invasive coronary angiography, revascularization, CAD diagnoses, and new prescriptions for aspirin and statins. Despite these differences, CCTA is not associated with a reduction in mortality or cardiac hospitalizations.


The sodium bile salt cotransport family SLC10.
The SLC10 family of sodium/bile salt cotransporters contains over 50 members in animal, plant and bacterial species. In man, two well-characterized members and three orphan transporters are known. The Na(+)/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile salt transporter (ASBT; SLC10A2) are critical components of the enterohepatic circulation of bile salts. NTCP and ASBT are cotransporters that mediate sodium-dependent, electrogenic uptake of mainly bile salts into hepatocytes (NTCP), biliary epithelial cells, ileal enterocytes and renal proximal tubular cells (ASBT).


[Mycobacterium kansasii lung infection and synchronous bronchopulmonary carcinoma].
The association of lung tuberculosis and carcinoma of the lung is very well-known, although it is exceptional the synchronous presentation of lung infection for nontuberculous mycobacteria and lung carcinoma. We present the case of a 41 year old male, smoker, with antecedents of lung tuberculosis in the adolescence and chronic liver disease for virus B and C that he presents fever, hoarseness and loss of 4 kg of weight of a month of evolution. The CT scan of the chest revealed a lung mass in left apex with pneumonitis, tumor invading chest wall and mediastinal lymph node enlargement. The biopsy of a supraclavicular node showed metastasis of squamous carcinoma, while in the sputum was isolated Mycobacterium kansasii sensitive to rifampin and ethambutol. HIV was negative. The possible mechanisms of this uncommon association are commented, next to a revision of the literature.


Spatial Patterning of Prey at Reproduction to Reduce Predation Risk: What Drives Dispersion from Groups?
Group living is a widespread behavior thought to be an evolutionary adaptation for reducing predation risk. Many group-living species, however, spend a portion of their life cycle as dispersed individuals, suggesting that the costs and benefits of these opposing behaviors vary temporally. Here, we evaluated mechanistic hypotheses for explaining individual dispersion as a tactic for reducing predation risk at reproduction (i.e., birthing) in an otherwise group-living animal. Using simulation analyses parameterized by empirical data, we assessed whether dispersion increases reproductive success by (i) increasing predator search time, (ii) reducing predator encounter rates because individuals are inconspicuous relative to groups, or (iii) eliminating the risk of multiple kills per encounter. Simulations indicate that dispersion becomes favorable only when detectability increases with group size and there is risk of multiple kills per encounter. This latter effect, however, is likely the primary mechanism driving females to disperse at reproduction because group detectability effects are presumably constant year-round. We suggest that the risk of multiple kills imposed by highly vulnerable offspring may be an important factor influencing dispersive behavior in many species, and conservation strategies for such species will require protecting sufficient space to allow dispersion to effectively reduce predation risk.


Mediastinal lymph node removal ameliorates cytotoxic T-lymphocyte functions in patients with non-small cell lung cancer.
Mediastinal lymph node (MLN) removal by video-assisted mediastinoscopic lymphadenectomy (VAMLA) for preoperative cancer staging was reported to be associated with increased survival. The aim of this study was to evaluate the immunologic effects of complete MLN removal by VAMLA on cytotoxic T lymphocyte (CTL) phenotype and function. Seventeen patients with non-small cell lung cancer (NSCLC) (stage cT1-4N0-3M0-1A) and 20 healthy participants were included in this study. Blood samples were collected before and 4 weeks after the procedure. Lymphocytes were isolated from the removed MLNs. CTL phenotypes and functions were evaluated by flow cytometry. Plasma levels of soluble programmed cell death protein 1 (sPD-1), soluble programmed cell death protein 1 ligand, and soluble CTL antigen 4 (sCTLA-4) were measured with enzyme-linked immunosorbent assay. The ratio of the immunosenescent CTLs (CD3+CD8+CD28-) was increased in peripheral blood and MLNs of the patients with NSCLC compared to controls (p = 0.037), and MLN removal did not change this ratio. PD-1 and CTL antigen 4 expressions were significantly reduced in peripheral blood CTLs after MLN removal by VAMLA (p = 0.01 and p = 0.01, respectively). Granzyme A expression was significantly reduced in the peripheral blood CTLs of the patients compared to controls (p = 0.006) and MLN removal by VAMLA significantly improved Granzyme A expression in CTLs (p = 0.003). Plasma concentrations of sPD-1 and sCTLA-4 remained unchanged after VAMLA. CTLs in the MLNs and peripheral blood of the patients with NSCLC had an immunosenescent phenotype, increased immune checkpoint receptor expression, and impaired cytotoxicity. MLN removal by VAMLA improved these phenotypic and functional characteristics of CTLs. These changes may explain the potential contribution of VAMLA to improved survival.


On the relations of phase separation and Hi-C maps to epigenetics.
The relationship between compartmentalization of the genome and epigenetics is long and hoary. In 1928, Heitz defined heterochromatin as the largest differentiated chromatin compartment in eukaryotic nuclei. Müller's discovery of position-effect variegation in 1930 went on to show that heterochromatin is a cytologically visible state of heritable (epigenetic) gene repression. Current insights into compartmentalization have come from a high-throughput top-down approach where contact frequency (Hi-C) maps revealed the presence of compartmental domains that segregate the genome into heterochromatin and euchromatin. It has been argued that the compartmentalization seen in Hi-C maps is owing to the physiochemical process of phase separation. Oddly, the insights provided by these experimental and conceptual advances have remained largely silent on how Hi-C maps and phase separation relate to epigenetics. Addressing this issue directly in mammals, we have made use of a bottom-up approach starting with the hallmarks of constitutive heterochromatin, heterochromatin protein 1 (HP1) and its binding partner the H3K9me2/3 determinant of the histone code. They are key epigenetic regulators in eukaryotes. Both hallmarks are also found outside mammalian constitutive heterochromatin as constituents of larger (0.1-5 Mb) heterochromatin-like domains and smaller (less than 100 kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes contributes to polymer-polymer phase separation that packages epigenetically heritable chromatin states during interphase. Contacts mediated by HP1 'bridging' are likely to have been detected in Hi-C maps, as evidenced by the B4 heterochromatic subcompartment that emerges from contacts between large KRAB-ZNF heterochromatin-like domains. Further, mutational analyses have revealed a finer, innate, compartmentalization in Hi-C experiments that probably reflect contacts involving smaller domains/complexes. Proteins that bridge (modified) DNA and histones in nucleosomal fibres-where the HP1-H3K9me2/3 interaction represents the most evolutionarily conserved paradigm-could drive and generate the fundamental compartmentalization of the interphase nucleus. This has implications for the mechanism(s) that maintains cellular identity, be it a terminally differentiated fibroblast or a pluripotent embryonic stem cell.


Multi-scale modeling of gene regulatory networks via integration of temporal and topological biological data.
Regulome is the dynamic network representation of the regulatory interplay among genes, proteins and other cellular components that control cellular processes. Reconstruction of gene regulatory networks (GRN) delineates one of the main objectives of Systems Biology towards understanding the organization of regulome. Significant progress has been reported the last years regarding GRN reconstruction methods, but the majority of them either consider information originating solely from gene expression data or/and are applied on a small fraction of the experimental dataset. In this paper, we will describe an integrative method, utilizing both temporal information arriving from time-series gene expression profiles, as well as topological properties of protein networks. The proposed methodology detects relations among either groups of genes or specific genes depending on the level of abstraction or resolution requested. Application on real data proved the ability of the method to extract relations in accordance with current biological knowledge as well as discriminate between different experimental conditions.


How cell wall complexity influences saccharification efficiency in Miscanthus sinensis.
The production of bioenergy from grasses has been developing quickly during the last decade, with Miscanthus being among the most important choices for production of bioethanol. However, one of the key barriers to producing bioethanol is the lack of information about cell wall structure. Cell walls are thought to display compositional differences that lead to emergence of a very high level of complexity, resulting in great diversity in cell wall architectures. In this work, a set of different techniques was used to access the complexity of cell walls of different genotypes of Miscanthus sinensis in order to understand how they interfere with saccharification efficiency. Three genotypes of M. sinensis displaying different patterns of correlation between lignin content and saccharification efficiency were subjected to cell wall analysis by quantitative/qualitative analytical techniques such as monosaccharide composition, oligosaccharide profiling, and glycome profiling. When saccharification efficiency was correlated negatively with lignin, the structural features of arabinoxylan and xyloglucan were found to contribute positively to hydrolysis. In the absence of such correlation, different types of pectins, and some mannans contributed to saccharification efficiency. Different genotypes of M. sinensis were shown to display distinct interactions among their cell wall components, which seem to influence cell wall hydrolysis.


Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery.
Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data, for the first time, indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.


Isotropic anomalous filtering in Diffusion-Weighted Magnetic Resonance Imaging.
Noise is inherent to Diffusion-Weighted Magnetic Resonance Imaging (DWI) and noise reduction methods are necessary. Although process based on classical diffusion is one of the most used approaches for digital image, anomalous diffusion has the potential for image enhancement and it has not been tested for DWI noise reduction. This study evaluates Anomalous Diffusion (AD) filter as DWI enhancement method. The proposed method was applied to magnetic resonance diffusion weighted images (DW-MRI) with different noise levels. Results show better performance for anomalous diffusion when compared to classical diffusion approach. The proposed method has shown potential in DWI enhancement and can be an important process to improve quality in DWI for neuroimage-based diagnosis.


Growth hormone secretory dynamics over the menstrual cycle.
Whether GH secretion in women varies over the menstrual cycle is uncertain. Previous investigations have led to conflicting conclusions; some studies suggested that there is an estrogen mediated rise in GH during the periovulatory (PO) and luteal (L) phases whereas others indicated no change in GH axis over the cycle. Differences in conclusions could relate to heterogeneity of the study populations, GH sampling paradigms or sensitivity of the GH assays used. In order to investigate whether GH secretion varied over the cycle, 24-h GH profiles using every 10-min sampling were obtained in 6 ovulatory women during the early follicular (EF), PO and L phases of the cycle. The TSH response to TRH, GH response to GRH and fasting plasma IGF-I were measured on each occasion. There was a trend toward higher integrated GH concentration (IGHC) during the PO phase, although this difference was not statistically significant (3284+/-721 vs 4542+/-872 vs 4071+/-699 microg/min/L; EF vs PO vs L; p=0.09). Similarly, deconvolution estimated GH secretion did not vary over the cycle (p=0.56). There were no differences in GH pulse amplitude or frequency. There were no correlations between IGHC and sex steroids. Serum IGF-I was constant over the cycle (272+/-38 vs 277+/-31 vs 265+/-38 microg/L; p=0.89). The TSH response to TRH and GH response to GRH did not vary over the cycle. We concluded that the effect of changes in the ovarian steroid milieu on the GH axis during spontaneous menstrual cycles is minimal.


Causes and evolutionary consequences of population subdivision of an Iberian mountain lizard, Iberolacerta monticola.
The study of the factors that influence population connectivity and spatial distribution of genetic variation is crucial for understanding speciation and for predicting the effects of landscape modification and habitat fragmentation, which are considered severe threats to global biodiversity. This dual perspective is obtained from analyses of subalpine mountain species, whose present distribution may have been shaped both by cyclical climate changes over ice ages and anthropogenic perturbations of their habitats. Here, we examine the phylogeography, population structure and genetic diversity of the lacertid lizard Iberolacerta monticola, an endemism considered to be facing a high risk of extinction in several populations. Northwestern quadrant of the Iberian Peninsula. We analyzed the mtDNA variation at the control region (454 bp) and the cytochrome b (598 bp) loci, as well as at 10 nuclear microsatellite loci from 17 populations throughout the distribution range of the species. According to nuclear markers, most sampling sites are defined as distinct, genetically differentiated populations, and many of them show traces of recent bottlenecks. Mitochondrial data identify a relatively old, geographically restricted lineage, and four to six younger geographically vicariant sister clades, whose origin may be traced back to the mid-Pleistocene revolution, with several subclades possibly associated to the mid-Bruhnes transition. Geographic range fragmentation of one of these clades, which includes lowland sites, is very recent, and most likely due to the accelerated loss of Atlantic forests by human intervention. Altogether, the data fit a "refugia within refugia" model, some lack of pattern uniformity notwithstanding, and suggest that these mountains might be the cradles of new species of Iberolacerta. However, the changes operated during the Holocene severely compromise the long-term survival of those genetic lineages more exposed to the anthropogenic perturbations of their habitats.


Amino acid sequence of the human fibronectin receptor.
The amino acid sequence deduced from cDNA of the human placental fibronectin receptor is reported. The receptor is composed of two subunits: an alpha subunit of 1,008 amino acids which is processed into two polypeptides disulfide bonded to one another, and a beta subunit of 778 amino acids. Each subunit has near its COOH terminus a hydrophobic segment. This and other sequence features suggest a structure for the receptor in which the hydrophobic segments serve as transmembrane domains anchoring each subunit to the membrane and dividing each into a large ectodomain and a short cytoplasmic domain. The alpha subunit ectodomain has five sequence elements homologous to consensus Ca2+-binding sites of several calcium-binding proteins, and the beta subunit contains a fourfold repeat strikingly rich in cysteine. The alpha subunit sequence is 46% homologous to the alpha subunit of the vitronectin receptor. The beta subunit is 44% homologous to the human platelet adhesion receptor subunit IIIa and 47% homologous to a leukocyte adhesion receptor beta subunit. The high degree of homology (85%) of the beta subunit with one of the polypeptides of a chicken adhesion receptor complex referred to as integrin complex strongly suggests that the latter polypeptide is the chicken homologue of the fibronectin receptor beta subunit. These receptor subunit homologies define a superfamily of adhesion receptors. The availability of the entire protein sequence for the fibronectin receptor will facilitate studies on the functions of these receptors.


[Prognostic value of peritoneal lavage cytology in gastric cancer].
The microscopic detection of free peritoneal tumour cells in peritoneal lavage fluid in gastric cancer patients is a useful predictor of peritoneal recurrence and poor prognosis. The aim of this study was to verify the prognostic significance of intraoperative peritoneal lavage cytology and its value as a predictor of peritoneal recurrence. We evaluated the presence of free peritoneal tumour cells with extemporary cytological examination in a series of 170 peritoneal washing samples from patients undergoing gastrectomy for gastric cancer over the period from January 1992 to June 2001. Twenty-eight patients (16%) had positive extemporary lavage cytology and there were no false-negatives as compared with the final examination. All patients with positive cytology presented serosal infiltration (T3/T4). Positive peritoneal lavage cytology was a predictor of poor prognosis and peritoneal recurrence: the 24 month survival rate was 17% for positive and 60% for negative cases (P = 0.003); in positive cases 71% of recurrences were located in the peritoneum. Intraoperative cytological examination of peritoneal washings can detect the presence of free malignant cells in the peritoneal cavity and can be used to select patients who may benefit from intraperitoneal chemotherapy.


Supervised exercises versus telerehabilitation. Benefits for persons with multiple sclerosis.
The purpose of this study was to investigate the effectiveness of structured telerehabilitation on fatigue, health status, quality of life (QoL), and activities of daily living (ADL) and compare the possible effects with structured supervised exercise programs in patients with Multiple Sclerosis. This study was a randomized, single-blind trial. Thirty patients with relapsing-remitting Multiple Sclerosis were included in the study and randomly divided into two groups; structured supervised exercise group (Group 1) and telerehabilitation group (Group 2). Group 1 (n = 15) completed a 12 week structured supervised exercise program. Group 2 (n = 15) completed a 12 week structured home-based exercise program. Patients were evaluated with functional independence measure (FIM), first section of Nottingham Health Profile (NHP-I), fatigue severity scale (FSS), and quality of life scale (QoLS) before and after the intervention. Significant differences were found in all parameters in both groups after the treatment (p < .05). No significant difference was found between groups regarding FIM-total, FIM-motor, FIM-cognitive, NHP sub-parameters, and QoLS (p > .05). Between-group differences revealed a significant difference in FSS and NHP total in favor of Group 1 (p < .05). A structured home-based exercise program can be an alternative to supervised exercises with no side effects in patients with multiple sclerosis. Home-based rehabilitation exercises that are checked and controlled through telerehabilitation can help patients improve their health-related QoL and ADL. However, supervised exercises can be more beneficial regarding the fatigue and health profile compared to the home-based exercises.


Exosome Precipitation by Ionic Strength Modulation: ExoPRISM.
Extracellular vesicles (EVs) are emerging as crucial materials for precision theragnostic applications. However, current separation methods are time-consuming, costly, and not scalable and deliver limited yields or purity. Here, we present EV precipitation by ionic strength modulation (ExoPRISM), a simple, low-cost, user-friendly, and readily adaptable approach for separating EVs in high yields without compromising their biological functions. Adding an electrolyte solution to blood plasma in small increments generates the sequential precipitation of proteins and EVs, allowing for fractional separation of EVs using low-speed centrifugation. The coprecipitated electrolytes are easily washed away, and the entire EV separation and washing process takes less than an hour. This approach successfully separates EVs from a broad range of volumes and types of biological fluids, including culture medium, urine, plasma, and serum, showing promise as a robust tool for next-generation liquid biopsies and regenerative medicine.


Monitoring extracellular pH, oxygen, and dopamine during reward delivery in the striatum of primates.
Dopamine projections that extend from the ventral tegmental area to the striatum have been implicated in the biological basis for behaviors associated with reward and addiction. Until recently, it has been difficult to evaluate the complex balance of energy utilization and neural activity in the striatum. Many techniques such as electrophysiology, functional magnetic resonance imaging (fMRI), and fast-scan cyclic voltammetry have been employed to monitor these neurochemical and neurophysiological changes. In this brain region, physiological responses to cues and rewards cause local, transient pH changes. Oxygen and pH are coupled in the brain through a complex system of blood flow and metabolism as a result of transient neural activity. Indeed, this balance is at the heart of imaging studies such as fMRI. To this end, we measured pH and O(2) changes with fast-scan cyclic voltammetry in the striatum as indices of changes in metabolism and blood flow in vivo in three Macaca mulatta monkeys during reward-based behaviors. Specifically, the animals were presented with Pavlovian conditioned cues that predicted different probabilities of liquid reward. They also received free reward without predictive cues. The primary detected change consisted of pH shifts in the striatal extracellular environment following the reward predicting cues or the free reward. We observed three types of cue responses that consisted of purely basic pH shifts, basic pH shifts followed by acidic pH shifts, and purely acidic pH shifts. These responses increased with reward probability, but were not significantly different from each other. The pH changes were accompanied by increases in extracellular O(2). The changes in pH and extracellular O(2) are consistent with current theories of metabolism and blood flow. However, they were of sufficient magnitude that they masked dopamine changes in the majority of cases. The findings suggest a role of these chemical responses in neuronal reward processing.


Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy.
To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.


Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases.
Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT), including Crohn's disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e.g., vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g., butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD/VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.