Extracting information from the power spectrum of synaptic noise.
In cortical neurons, synaptic "noise" is caused by the nearly random release of thousands of synapses. Few methods are presently available to analyze synaptic noise and deduce properties of the underlying synaptic inputs. We focus here on the power spectral density (PSD) of several models of synaptic noise. We examine different classes of analytically solvable kinetic models for synaptic currents, such as the "delta kinetic models," which use Dirac delta functions to represent the activation of the ion channel. We first show that, for this class of kinetic models, one can obtain an analytic expression for the PSD of the total synaptic conductance and derive equivalent stochastic models with only a few variables. This yields a method for constraining models of synaptic currents by analyzing voltage-clamp recordings of synaptic noise. Second, we show that a similar approach can be followed for the PSD of the the membrane potential (Vm) through an effective-leak approximation. Third, we show that this approach is also valid for inputs distributed in dendrites. In this case, the frequency scaling of the Vm PSD is preserved, suggesting that this approach may be applied to intracellular recordings of real neurons. In conclusion, using simple mathematical tools, we show that Vm recordings can be used to constrain kinetic models of synaptic currents, as well as to estimate equivalent stochastic models. This approach, therefore, provides a direct link between intracellular recordings in vivo and the design of models consistent with the dynamics and spectral structure of synaptic noise.


In DRG11 knock-out mice, trigeminal cell death is extensive and does not account for failed brainstem patterning.
A previous study (Ding et al., 2003) showed that the homeodomain transcription factor DRG11 is necessary for pattern formation in the trigeminal nucleus principalis (PrV), the requisite brainstem nucleus for development of the whisker-to-barrel cortex pathway. However, it is not known how DRG11 contributes to pattern formation. Anatomical studies were performed in DRG11 knock-out (-/-) and DRG11/Bax double -/- mice to test the hypotheses that DRG11 is required for neuronal survival in the V pathway and that PrV cell death is sufficient to explain pattern alterations. At birth, DRG11(-/-) mice had equivalent cell loss in the V ganglion, PrV, and spinal V subnucleus interpolaris (SpVi). Because whisker-related patterns were normal in the SpVi, cell death would not appear to explain failed pattern formation in the mutant PrV. Electron microscopy revealed exuberant apoptosis and necrosis as the mechanisms of PrV cell death occurring in the late prenatal and newborn DRG11(-/-), when such cell death was up to six times more prevalent than normal. DRG11 heterozygote and Bax(-/-) mice were crossed in an attempt to dissociate PrV patterning anomalies from exuberant apoptosis in DRG11(-/-) mice. Both DRG11(-/-) and DRG11/Bax double -/- mutants lacked whisker-related patterning in their PrV, despite Bax(-/-)-induced rescue of V ganglion and PrV cells. Thus, apoptotic cell death is not a sufficient cause of failed pattern formation in the PrV of the DRG11(-/-). A signaling pathway involving DRG11 may, therefore, be the elusive PrV pattern maker.


Surface ultrastructure of collagen fibrils and their association with proteoglycans in human cornea and sclera by atomic force microscopy and energy-filtering transmission electron microscopy.
We aimed to investigate the possible association of proteoglycans with D-periodic collagen fibrils in the human cornea and sclera, using energy-filtering transmission electron microscopy (EF-TEM) and atomic force microscopy (AFM). Human cornea and sclera were digested with keratanase to eliminate keratan sulfate proteoglycans (KSPGs). For EF-TEM observation, surface proteoglycans were detected by cupromeronic blue (CB) staining. For AFM observation, cornea and sclera were treated with sodium hydroxide before and after keratanase digestion, and the surface topology of collagen fibrils was analyzed. With CB staining, numerous CB-positive short filaments of surface proteoglycans (proteoglycan filaments) were observed in the interfibrillar spaces of cornea and sclera associated with collagen fibrils. AFM imaging showed that the depth and periodicity of D-periodic collagen fibrils in keratanase-treated corneal collagens were deeper and more regular than in untreated ones. Moreover, the depth and periodicity of keratanase-untreated corneal collagens were shallow and irregular in comparison with keratanase-untreated scleral collagens. On the other hand, there was no difference in depth or regularity between keratanase-treated and -untreated scleral collagen fibrils. Using AFM imaging, additional thin grooves sub-bands were detected on the surface of keratanase-treated corneal collagen fibrils. The grooves were not detected in keratanase-untreated collagen fibrils nor in scleral collagen fibrils with or without keratanase digestion. Comparing densitometry waves, the grooves of D-periodic corneal collagen sub-bands corresponded to a and c bands. Using AFM and EF-TEM to study corneal and scleral collagen fibrils and their association with proteoglycans, we conclude that KSPG is found in ample amounts in the human cornea in comparison with sclera. Moreover, we topologically detected KSPG attached to a and c bands of collagen fibrils.


Hierarchical learning induces two simultaneous, but separable, prediction errors in human basal ganglia.
Studies suggest that dopaminergic neurons report a unitary, global reward prediction error signal. However, learning in complex real-life tasks, in particular tasks that show hierarchical structure, requires multiple prediction errors that may coincide in time. We used functional neuroimaging to measure prediction error signals in humans performing such a hierarchical task involving simultaneous, uncorrelated prediction errors. Analysis of signals in a priori anatomical regions of interest in the ventral striatum and the ventral tegmental area indeed evidenced two simultaneous, but separable, prediction error signals corresponding to the two levels of hierarchy in the task. This result suggests that suitably designed tasks may reveal a more intricate pattern of firing in dopaminergic neurons. Moreover, the need for downstream separation of these signals implies possible limitations on the number of different task levels that we can learn about simultaneously.


Exploiting Intermolecular Interactions between Alkyl-Functionalized Redox-Active Molecule Pairs to Enhance Interfacial Electron Transfer.
The strategies to enhance electron transfer rates between redox-active, light-harvesting molecules attached to semiconductor surfaces and redox mediators in solution by modifying molecular structure are not fully investigated yet. Therefore, the design of molecules with controlled electron transfer rates remains a challenge. The aims of this work are to quantify the effect of long alkyl chain substitution on the electron transfer from cobalt(II/III) tris(2,2'-bipyridine) to organic molecules containing carbazole and thiophene and to demonstrate that alkyl chains can be used to enhance electron transfer between donor-acceptor pairs. To this end, we study the effect of using a combination of donor and acceptor molecules with and without alkyl chains on electron transfer kinetics. Using transient absorption spectroscopy, we show that when only the molecules or the mediators have long alkyl chains, electron transfer is slightly blocked as expected. Counterintuitively, electron transfer is up to 13 times faster when long alkyl chains are attached to both the redox-active molecules and the redox mediators. The faster electron transfer is explained by an alkyl-alkyl chain interaction between the donor/acceptor, leading to the proximity (trapping) of the redox mediators close to the π-conjugated backbone of the molecules. These results suggest that intermolecular interactions can be used to enhance the electron transfer rates significantly even with well-established insulating alkyl chains attached to molecules without changing the electrochemical driving force.


Different gaze strategies during eye versus hand tracking of a moving target.
The ability to visually track, using smooth pursuit eye movements, moving objects is critical in both perceptual and action tasks. Here, by asking participants to view a moving target or track it with their hand, we tested whether different task demands give rise to different gaze strategies. We hypothesized that during hand tracking, in comparison to eye tracking, the frequency of catch-up saccades would be lower, and the smooth pursuit gain would be greater, because it limits the loss of stable retinal and extra-retinal information due to saccades. In our study participants viewed a visual target that followed a smooth but unpredictable trajectory in a horizontal plane and were instructed to either track the target with their gaze or with a cursor controlled by a manipulandum. Although the mean distance between gaze and target was comparable in both tasks, we found, consistent with our hypothesis, an increase in smooth pursuit gain and a decrease in the frequency of catch-up saccades during hand tracking. We suggest that this difference in gaze behavior arises from different tasks demands. Whereas keeping gaze close to the target is important in both tasks, obtaining stable retinal and extra-retinal information is critical for guiding hand movement.


Crystal structures of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) monohydrate and fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) methanol hemisolvate: rhodium structures that are isotypic with their iridium analogs.
The crystal structures of two solvates of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) are reported, i.e. one with water in the crystal lattice, fac-[RhCl3(Me3P)3]·H2O, and one with methanol in the crystal lattice, fac-[RhCl3(Me3P)3]·0.5CH3OH. These rhodium compounds exhibit distorted octahedral coordination spheres at the metal and are isotypic with the analogous iridium compounds previously reported by us [Merola et al. (2013 ▶). Polyhedron, 54, 67-73]. Comparison is made between the rhodium and iridium compounds, highlighting their isostructural relationships.


Recommendations from recent graduates in medicine, nursing and pharmacy on improving interprofessional education in university programs: a qualitative study.
Interprofessional education (IPE) has been recognized as an innovative approach for the development of a collaborative, practice-ready health workforce, but is not used consistently in undergraduate health professional programs. We sought to explore the reflections of graduates on the IPE experiences they had during their undergraduate education and training. It was anticipated that having completed their pre-vocational education and spent up to two years working in a clinical environment, recent graduates would be well-placed to provide insights into the value of the IPE opportunities they had, and to suggest approaches for improving these opportunities in undergraduate programs. This study was part of a larger research project (Interprofessional Education for the Quality use of Medicines; IPE for QuM) which used focus groups as part of an interpretive research design to inform other aspects of the research. Here, we report on focus groups with recent graduates recruited from area health services across Australia. Sixty-eight recent graduates working in New South Wales, Western Australia, and Tasmania participated in 12 focus group sessions. In this paper, we report on new graduates' reflections on their experiences of IPE as part of their university degree, as well as their recommendations to improve interprofessional education before graduation. The new graduates were unanimous in valuing IPE from their current perspective of being in the health workforce. Most IPE experiences recalled were regarded as positive, but those valued most highly were experiences that involved genuine engagement and opportunities to interact with students in other professions working on a relevant problem. Clinical placement was a missed opportunity with few structured meaningful interprofessional learning experiences. Surprisingly there was little social contact between professions in universities even when programs were co-located, thus reinforcing professional silos. The graduates provided many insightful reflections about the value of university-based IPE and their preparedness for clinical practice. Although universally acclaimed as a "good idea" there is much room for improvement. We put forward a set of suggestions to improve IPE and guide the design of future IPE efforts.


Self-reported medication and herb/supplement use by women with and without fibromyalgia.
Using a telephone survey of 434 women who self-reported having and 198 women, who denied having fibromyalgia (FM) (aged 18-80 years), we compared women on self-reported number, major types, and effectiveness of currently taken conventional medications and herbs/supplements. Ninety-three percent of women with FM reported taking at least one medication (1855 total, 499 types, on average 4.6 per person) compared with 56% of women without FM (269 total, 172 types, 1.4 per person on average). Half (n = 217) of the women with FM reported taking antidepressant drugs; more reported selective serotonin reuptake inhibitors (SSRI)-type with moderate effectiveness than tricyclic amines deemed to have strong effectiveness. Few were taking dual uptake inhibitors or the now approved pregabalin. Nearly 30% reported taking nonsteroidal anti-inflammatory drugs (NSAID), which have weak efficacy evidence. Less than 8% of controls reported taking either antidepressants or NSAID. Having FM was associated with these medications plus guaifenesen, anticonvulsants, muscle relaxants, narcotics, other analgesics, and benzodiazepines. Highest effectiveness scores were for opioid narcotics and guaifenesin. Forty-three percent of women with FM reported taking at least one herb/supplement compared with 23% of control women. The most common types were omega esterified fatty acids, glucosamine, and gingko. No particular type distinguished between the groups. Both groups tended to rate overall effectiveness lower for herbs/supplements than for conventional medications. Substantial numbers of women with FM were taking pain medications that often lacked evidence for effectiveness. The variety of medications being taken by women with FM compared with women without FM indicates that there are few medications that consistently provide symptom alleviation for this condition.


Exploring person-centredness: a qualitative meta-synthesis of four studies.
Person-centredness as a concept is becoming more prominent and increasingly central within some research literature, approaches to practice and as a guiding principle within some health and social care policy. Despite the increasing body of literature into person-centred nursing (PCN), there continues to be a 'siloed' approach to its study, with few studies integrating perspectives from across nursing specialties. The purpose of this paper is to present the results of a study undertaken to explore if the secondary analysis of findings from four different and unrelated research studies (that did not have the main aim of researching person-centredness) could inform our understanding of person-centred nursing. A qualitative meta-synthesis was undertaken of the data derived from the four unrelated research studies undertaken with different client groups with long-term health conditions. A hermeneutic and interpretative approach was used to guide the analysis of data and framed within a particular person-centred nursing framework. Findings suggest 'professional competence' (where competence is understood more broadly than technical competence) and knowing 'self' are important prerequisites for person-centred nursing. Characteristics of the care environment were also found to be critical. Despite the existence of expressed person-centred values, care processes largely remained routinised, ritualistic and affording few opportunities for the formation of meaningful relationships. Person-centred nursing needs to be understood in a broader context than the immediate nurse-patient/family relationship. The person-centred nursing framework has utility in helping to understand the dynamics of the components of person-centredness and overcoming the siloed nature of many current perspectives.


Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease.
Mitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. The frequency of affected mothers of the proband with PD (83/167, 49.4%) was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4%) (Odds Ratio 1.22; 95%CI 0.83-1.81). After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic mDNA mutations, contribute to the risk of familial PD.


Management of paediatric spontaneous pneumothorax: a multicentre retrospective case series.
Paediatric guidelines are lacking for management of spontaneous pneumothorax. Adult patient-focused guidelines (British Thoracic Society 2003 and 2010) introduced aspiration as first-line intervention for primary spontaneous pneumothorax (PSP) and small secondary spontaneous pneumothoraces (SSP). Paediatric practice is unclear, and evidence for aspiration success rates is urgently required to develop paediatric-specific recommendations. Retrospective analysis of PSP and SSP management at nine paediatric emergency departments across Australia and New Zealand (2003-2010) to compare PSP and SSP management. 219 episodes of spontaneous pneumothorax occurred in 162 children (median age 15 years, 71% male); 155 PSP episodes in 120 children and 64 SSP episodes in 42 children. Intervention in PSP vs SSP episodes occurred in 55% (95% CI 47% to 62%) vs 70% (60% to 79%), p<0.05. An intercostal chest catheter (ICC) was used in 104/219 (47%) episodes. Aspiration was used in more PSP than in SSP episodes with interventions (27% (18% to 37%) vs 9% (3% to 21%), p<0.05). Aspiration success was 52% (33% to 70%) overall and not significantly different between PSP and SSP. Aspiration success was greater in small vs large pneumothoraces (80% (48% to 95%) vs 33% (14% to 61%), p=0.01). Small-bore ICCs were used in 40% of ICCs and usage increased during the study. In this descriptive study of pneumothorax management, PSP and SSP management did not differ and ICC insertion was the continuing preferred intervention. Overall success of aspiration was lower than reported results for adults, although success was greater for small than for large pneumothoraces. Paediatric prospective studies are urgently required to determine optimal paediatric interventional management strategies.


Solvent signal suppression for high-resolution MAS-DNP.
Dynamic nuclear polarization (DNP) has become a powerful tool to substantially increase the sensitivity of high-field magic angle spinning (MAS) solid-state NMR experiments. The addition of dissolved hyperpolarizing agents usually results in the presence of solvent signals that can overlap and obscure those of interest from the analyte. Here, two methods are proposed to suppress DNP solvent signals: a Forced Echo Dephasing experiment (FEDex) and TRAnsfer of Populations in DOuble Resonance Echo Dephasing (TRAPDORED) NMR. These methods reintroduce a heteronuclear dipolar interaction that is specific to the solvent, thereby forcing a dephasing of recoupled solvent spins and leaving acquired NMR spectra free of associated resonance overlap with the analyte. The potency of these methods is demonstrated on sample types common to MAS-DNP experiments, namely a frozen solution (of l-proline) and a powdered solid (progesterone), both containing deuterated glycerol as a DNP solvent. The proposed methods are efficient, simple to implement, compatible with other NMR experiments, and extendable past spectral editing for just DNP solvents. The sensitivity gains from MAS-DNP in conjunction with FEDex or TRAPDORED then permits rapid and uninterrupted sample analysis.


Elective oophorectomy for benign gynecological disorders.
To review the risks and benefits of elective oophorectomy and to make a clinical recommendation for an appropriate age when benefits of this procedure outweigh the risks. The risks and benefits of oophorectomy as detailed in published articles are reviewed with regard to quality-of-life issues and mortality outcomes in oophorectomized versus non-oophorectomized women from five diseases linked to ovarian hormones (coronary heart disease, ovarian cancer, breast cancer, stroke, and hip fracture). Numerous reports link oophorectomy to higher rates of cardiovascular disease, osteoporosis, hip fractures, dementia, short-term memory impairment, decline in sexual function, decreased positive psychological well-being, adverse skin and body composition changes, and adverse ocular changes, as well as more severe hot flushes and urogenital atrophy. The potential benefits associated with oophorectomy include prevention of ovarian cancer, a decline in breast cancer risk, and a reduced risk of pelvic pain and subsequent ovarian surgery. In our study of long-term mortality after oophorectomy using Markov modeling, preservation of ovaries until women are at least aged 65 years was associated with higher survival rates. For women between ages 50 and 54 with hysterectomy and ovarian preservation, the probability of surviving to age 80 was 62% versus 54% if oophorectomy was performed. This 8% difference in survival is primarily due to fewer women dying from cardiovascular heart disease and/or hip fracture. This survival advantage far outweighs the 0.47% increased mortality rate from ovarian cancer prevented by oophorectomy. If surgery occurred between ages 55 and 59, the survival advantage was 4%. After age 64 there were no significant differences in survival rates. Prior literature supports our conclusion of a benefit over risk for ovarian conservation. Elective oophorectomy is associated with short-and long-term health consequences that merit serious consideration. For women with an average risk of ovarian cancer, ovarian conservation until at least age 65 seems to benefit long-term survival.


Parenteral treatment of clinical mastitis with tylosin base or penethamate hydriodide in dairy cattle.
The objective of this study was to compare the clinical and bacteriological cure rates of cows with clinical mastitis following treatment with either tylosin base (5 g injected 3 times at 24-h intervals; n = 306) or penethamate hydriodide (5 g injected 3 times at 24-h intervals; n = 289). Duplicate milk samples were collected before treatment and again 14 +/- 3 and 21 +/- 3 d later for microbiological analysis. Only those quarters from which gram-positive mastitis pathogens were isolated before treatment were included in the analyses. Streptococcus uberis was the most prevalent isolate. The number of cows with clinical failure (i.e., retreated within 21 d of enrollment) did not differ between treatments (64 vs. 63, respectively). At the quarter level, there was no difference in the proportion of bacteriological cure between treatments (81.2 vs. 83.8% for penethamate hydriodide or tylosin, respectively). The proportions of clinical and bacteriological cure were influenced by age, herd, severity of mastitis, number of glands within the cow with clinical mastitis, bacterial species, and days postpartum at enrollment. There was no difference between treatment groups for SCC (4.46 vs. 4.44 +/- 0.08, mean +/- standard error of the difference in ln SCC for cows treated with penethamate hydriodide or tylosin, respectively) or production of milk solids (1.45 vs. 1.48 +/- 0.02 kg/d of milk fat + protein, for the penethamate hydriodide or tylosin treatment, respectively). Overall, there was no difference in the proportions of clinical failure (17.3 vs. 16.5% of cows treated with penethamate hydriodide or tylosin, respectively) or bacteriological cure (79.8 vs. 82.0% of cows treated with penethamate hydriodide or tylosin, respectively), or in SCC or milk production between dairy cows with clinical mastitis and those treated for clinical mastitis with 1 of 2 parenteral antibiotic therapies.


A quantitative XANES analysis of the calcium high-affinity binding site of the purple membrane.
In this article we report x-ray absorption measurements of Ca(2+)-substituted bacteriorhodopsin. We present a detailed study of the absorption spectrum close to the absorption edge that is very sensitive to the site geometry. We combined ab initio calculations of the x-ray absorption cross section based on a full multiple scattering approach, with a best fit of the experimental data performed by changing the cluster geometry. The Ca(2+)-bacteriorhodopsin environment is composed of six oxygen atoms showing a distorted orthorhombic symmetry, whereas the Ca(2+) in water solution has a regular octahydrated first sphere of coordination. Our results are in good agreement with previous molecular models suggesting that the high-affinity cationic site could be in the proximity of the retinal pocket. Our results provide strong direct evidence of the specific binding site of the metal cation in bacteriorhodopsin.


Chronic health impairment due to 2,3,7,8-tetrachloro-dibenzo-p-dioxin exposure.
The aim of this study, performed in 2008, was to evaluate the consequences of severe occupational intoxication with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) that occurred during production of the herbicide trichlorophenoxyacetic acid in the period 1965-1968. Examination of 11 men, mean age 64.4+/-1.5 years, included: internal and neurological examination, eye fundus examination, TCDD in plasma, thyroid-stimulating hormone (TSH), testosterone and serum lipids, ultrasonography of the carotid artery, nerve conduction study (NCS), electroencephalography (EEG), visual evoked potential (VEP), Lanthony test of acquired visual impairment, single photon emission computer tomography (SPECT) of the brain, neuropsychological examination and carbohydrate-deficient transferrin (CDT), a marker of chronic ethanol intake. Mean TCDD level in 2008 was still 274.0+/-181.2 pg/g blood lipids (reference level is 2-3 pg/g). All (100%) patients had residues of chloracne/chloracne consequences, atherosclerotic changes on the eye fundus and plaques in the carotid arteries. Progression of intima-media thickness (IMT) from a mean of 0.84+/-0.14 mm in 2003 to 1.09+/-0.18 mm in 2008 was observed. Ninety-one per cents of patients had impairment in SPECT of the brain; and 55% of patients had hyperfixation of the perfusion indicator as a measure of increased neuronal activity. Additionally, 91 % of patients were treated for hyperlipidaemia, 73 % for hypertension, 55 % for diabetes type 2, 45 % for ischemic heart disease, and 36 % for psychological disorders. The Lanthony test demonstrated acquired dyschromatopsia in 80 % of patients. Mean colour confusion index (CCI) was 1.438, which indicates impairment since 2003, when the index was 1.302. CDT was in the normal range and did not correlate with CCI. Neuropsychological status appeared stabilized in all 8 patients examined, with impairment in one or more parameter (memory, attention, verbal fluency, psychomotor speed, motorics) in comparison to the norm. Forty years after intoxication, the blood level of TCDD is still 100 times higher than in the general population. Other PCDD/Fs were not elevated. A high percentage of subjects suffer from neurological and vascular disorders. No association of alcohol consumption with neurological impairment was seen, and the highly significant correlation between CCI and TCDD blood concentration suggests that acquired colour impairment was associated with TCDD but not with alcohol consumption. IMT significantly increased during past 5 years. The patients obviously need complex treatment, including intense hypolipidaemic and antidepressant therapy.


Race and trust in the health care system.
A legacy of racial discrimination in medical research and the health care system has been linked to a low level of trust in medical research and medical care among African Americans. While racial differences in trust in physicians have been demonstrated, little is known about racial variation in trust of health insurance plans and hospitals. For the present study, the authors analyzed responses to a cross-sectional telephone survey to assess the independent relationship of self-reported race (non-Hispanic black or non-Hispanic white) with trust in physicians, hospitals, and health insurance plans. Respondents ages 18-75 years were asked to rate their level of trust in physicians, health insurance plans, and hospitals. Items from the Medical Mistrust Index were used to assess fear and suspicion of hospitals. Responses were analyzed for 49 (42%) non-Hispanic black and 69 (58%) non-Hispanic white respondents (N=118; 94% of total survey population). A majority of respondents trusted physicians (71%) and hospitals (70%), but fewer trusted their health insurance plans (28%). After adjustment for potential confounders, non-Hispanic black respondents were less likely to trust their physicians than non-Hispanic white respondents (adjusted absolute difference 37%; p=0.01) and more likely to trust their health insurance plans (adjusted absolute difference 28%; p=0.04). The difference in trust of hospitals (adjusted absolute difference 13%) was not statistically significant. Non-Hispanic black respondents were more likely than non-Hispanic white respondents to be concerned about personal privacy and the potential for harmful experimentation in hospitals. Patterns of trust in components of our health care system differ by race. Differences in trust may reflect divergent cultural experiences of blacks and whites as well as differences in expectations for care. Improved understanding of these factors is needed if efforts to enhance patient access to and satisfaction with care are to be effective.


Affecting perceptions of harm and addiction among college waterpipe tobacco smokers.
The spread of waterpipe tobacco use among youth may be due in part to perceptions that waterpipe tobacco use is safer than other tobacco products, such as cigarettes. In two pilot studies, we sought to modify college waterpipe smokers' perceived risks and worry about waterpipe tobacco smoking. We conducted two web-based studies that varied whether college waterpipe users received information on (a) spread of and use of flavored tobacco in waterpipe and (b) harms of waterpipe smoking. Study 1 (N = 91) tested the "incremental" effects on perceptions of risk and worry of adding information about harms of waterpipe smoking to information on the spread of waterpipe and use of flavorings in the tobacco. Study 2 (N = 112) tested the effects on perceptions of risk and worry of reviewing information about harms of waterpipe smoking compared to a no information control group. In Study 1 only, we assessed as part of a 6-month follow-up (n = 70) the percentage of participants who reported no longer using waterpipe. Pooling data from both studies, participants who received information about the harms of waterpipe smoking reported greater perceived risk and worry about harm and addiction and expressed a stronger desire to quit. In Study 1, 62% of participants in the experimental group versus 33% in the control group reported having stopped waterpipe use. These are the first studies to show that perceptions of addiction and harm from waterpipe use can be modified using minimally intensive interventions; such interventions show promise at decreasing waterpipe use.


SHOULDER EXTERNAL ROTATOR ECCENTRIC TRAINING VERSUS GENERAL SHOULDER EXERCISE FOR SUBACROMIAL PAIN SYNDROME: A RANDOMIZED CONTROLLED TRIAL.
Shoulder pain affects up to 67% of the population at some point in their lifetime with subacromial pain syndrome (SAPS) representing a common etiology. Despite a plethora of studies there remains conflicting evidence for appropriate management of SAPS. To compare outcomes, for individuals diagnosed with SAPS, performing a 6-week protocol of eccentric training of the shoulder external rotators (ETER) compared to a general exercise (GE) protocol. Randomized controlled trial. Forty-eight individuals (mean age 46.8 years + /-17.29) with chronic shoulder pain, and a clinical diagnosis of SAPS were randomized into either an experimental group performing ETER or a control group performing a GE program. The intervention lasted for six weeks, and outcomes were measured after three weeks, six weeks, and again at six months post intervention. The primary outcome of function, measured by the Western Ontario Rotator Cuff Index, demonstrated a significant interaction effect derived from a multilevel hierarchical model accounting for repeated measures favoring the experimental group at week 3: 14.65 (p=.003), Week 6: 17.04 (p<.001) and six months: 15.12 (p=.007). After six months, secondary outcome measures were improved for Numeric Pain Rating Scale levels representing pain at worst (p=.006) and pain on average (p=0.02), external rotator (p<.001), internal rotator (p=0.02), and abductor strength (p<.001). There were no statistically significant differences in secondary outcome measures of Global Rating of Change, Active Range of Motion, the Upper Quarter Y Balance Test and strength ratios after six months. An eccentric program targeting the external rotators was superior to a general exercise program for strength, pain, and function after six months. The findings suggest eccentric training may be efficacious to improve self-report function and strength for those with SAPS. 2b.


Mapping the cellular electrophysiology of rat sympathetic preganglionic neurones to their roles in cardiorespiratory reflex integration: a whole cell recording study in situ.
Sympathetic preganglionic neurones (SPNs) convey sympathetic activity flowing from the CNS to the periphery to reach the target organs. Although previous in vivo and in vitro cell recording studies have explored their electrophysiological characteristics, it has not been possible to relate these characteristics to their roles in cardiorespiratory reflex integration. We used the working heart-brainstem preparation to make whole cell patch clamp recordings from T3-4 SPNs (n = 98). These SPNs were classified by their distinct responses to activation of the peripheral chemoreflex, diving response and arterial baroreflex, allowing the discrimination of muscle vasoconstrictor-like (MVC(like), 39%) from cutaneous vasoconstrictor-like (CVC(like), 28%) SPNs. The MVC(like) SPNs have higher baseline firing frequencies (2.52 ± 0.33 Hz vs. CVC(like) 1.34 ± 0.17 Hz, P = 0.007). The CVC(like) have longer after-hyperpolarisations (314 ± 36 ms vs. MVC(like) 191 ± 13 ms, P < 0.001) and lower input resistance (346 ± 49 MΩ vs. MVC(like) 496 ± 41 MΩ, P < 0.05). MVC(like) firing was respiratory-modulated with peak discharge in the late inspiratory/early expiratory phase and this activity was generated by both a tonic and respiratory-modulated barrage of synaptic events that were blocked by intrathecal kynurenate. In contrast, the activity of CVC(like) SPNs was underpinned by rhythmical membrane potential oscillations suggestive of gap junctional coupling. Thus, we have related the intrinsic electrophysiological properties of two classes of SPNs in situ to their roles in cardiorespiratory reflex integration and have shown that they deploy different cellular mechanisms that are likely to influence how they integrate and shape the distinctive sympathetic outputs.


Species co-occurrence networks: Can they reveal trophic and non-trophic interactions in ecological communities?
Co-occurrence methods are increasingly utilized in ecology to infer networks of species interactions where detailed knowledge based on empirical studies is difficult to obtain. Their use is particularly common, but not restricted to, microbial networks constructed from metagenomic analyses. In this study, we test the efficacy of this procedure by comparing an inferred network constructed using spatially intensive co-occurrence data from the rocky intertidal zone in central Chile to a well-resolved, empirically based, species interaction network from the same region. We evaluated the overlap in the information provided by each network and the extent to which there is a bias for co-occurrence data to better detect known trophic or non-trophic, positive or negative interactions. We found a poor correspondence between the co-occurrence network and the known species interactions with overall sensitivity (probability of true link detection) equal to 0.469, and specificity (true non-interaction) equal to 0.527. The ability to detect interactions varied with interaction type. Positive non-trophic interactions such as commensalism and facilitation were detected at the highest rates. These results demonstrate that co-occurrence networks do not represent classical ecological networks in which interactions are defined by direct observations or experimental manipulations. Co-occurrence networks provide information about the joint spatial effects of environmental conditions, recruitment, and, to some extent, biotic interactions, and among the latter, they tend to better detect niche-expanding positive non-trophic interactions. Detection of links (sensitivity or specificity) was not higher for well-known intertidal keystone species than for the rest of consumers in the community. Thus, as observed in previous empirical and theoretical studies, patterns of interactions in co-occurrence networks must be interpreted with caution, especially when extending interaction-based ecological theory to interpret network variability and stability. Co-occurrence networks may be particularly valuable for analysis of community dynamics that blends interactions and environment, rather than pairwise interactions alone.


Perceived changes in adult family members' roles and responsibilities during critical illness.
An exploratory design was used to study the effects of critical care hospitalization on family roles and responsibilities of adult family members and how these effects changed over time. A convenience sample of 52 subjects from pediatric, neonatal, surgical, medical, and cardiovascular intensive care units was used. Data were collected using an open-ended question contained in the Iowa ICU Family Scale (IIFS). Using qualitative techniques, seven themes were identified: (a) Pulling together, (b) Fragmentation of families, (c) Increased dependence, (d) Increased independence, (e) Increased responsibilities, (f) Change in routine, and (g) Change in feelings. These findings indicate that nurses need to implement family-centered interventions such as role supplementation programs or identification of support systems to decrease role strain and role overload in families during a crisis.


Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small-cell lung cancer in patients with viral hepatitis: a case series.
Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in patients with metastatic melanoma. Limited evidence exists on the safety and efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections as these patients have traditionally been excluded from clinical trials because of a theoretical risk of immune reconstitution inflammatory syndrome. We aim to determine the safety and efficacy of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for either metastatic melanoma or metastatic NSCLC in the setting of chronic or past HBV/HCV infection. The safety and efficacy of treatment were analysed retrospectively by examining response to treatment, alanine transaminase (ALT) trends and viral load trends. One patient showed an increase in ALT of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to the normal range following treatment of his HCV infection with ledipasvir 90 mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of CTCAE grade 1 severity. The remaining two patients experienced no hepatic toxicity, with stable disease continuing after more than 24 cycles of nivolumab. Efficacy was similar to the data of published trials. Our results indicate that patients with metastatic melanoma and NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.


Crystallinity enhancement of Nafion electrolyte membranes assisted by a molecular gelator.
Nanocrystallites, acting as physical cross-links in Nafion membranes, play a crucial role in building blocks for improving mechanical durability and stopping fuel crossover. However, Nafion membranes suffer from low crystallinity due to the irregular pendent side chains, which hinder self-aggregation of the poly(tetrafluoroethylene) (PTFE) backbones. For the first time, a molecular gelator was introduced in the membrane casting process to enhance the rate of self-assembly of PTFE backbones so as to increase the membrane's crystallinity as well as proton conductivity without sacrificing the purity of Nafion. The molecular gelator used was 3,4-dimethylbenzaldehyde (DMBA). Addition of 0.5 wt % DMBA led to a 42% increase in crystallinity, a 32% increase in yield strength, a 22% increase in tensile modulus and an 18% increase in proton conductivity at 60 °C and 90% relative humidity. Additionally, the membrane electrode assembly (MEA) prepared from the membranes cast from the solution containing 0.5 wt % DMBA also showed an increase of 17% in maximum power density in comparison to the MEA prepared from pure Nafion membrane in a single cell polarization test without any external humidification. Transmission electron microscopy (TEM) and molecular dynamics simulation were used to elucidate the structural changes in Nafion membrane due to the introduction of DMBA. It was observed that the presence of DMBA gives wider crystalline regions under TEM. The molecular dynamics simulation at 500 K shows that the PTFE backbones become elongated in the presence of DMBA due to the enhanced mobility. This is consistent with the observed increase in crystallinity in the membrane as it means reduced entropic change upon crystallization.


Regulation of gene expression by PI3K in mouse growth plate chondrocytes.
Endochondral ossification, the process through which long bones are formed, involves chondrocyte proliferation and hypertrophic differentiation in the cartilage growth plate. In a previous publication we showed that pharmacological inhibition of the PI3K signaling pathway results in reduced endochondral bone growth, and in particular, shortening of the hypertrophic zone in a tibia organ culture system. In this current study we aimed to investigate targets of the PI3K signaling pathway in hypertrophic chondrocytes. Through the intersection of two different microarray analyses methods (classical single gene analysis and GSEA) and two different chondrocyte differentiation systems (primary chondrocytes treated with a pharmacological inhibitor of PI3K and microdissected growth plates), we were able to identify a high number of genes grouped in GSEA functional categories regulated by the PI3K signaling pathway. Genes such as Phlda2 and F13a1 were down-regulated upon PI3K inhibition and showed increased expression in the hypertrophic zone compared to the proliferative/resting zone of the growth plate. In contrast, other genes including Nr4a1 and Adamts5 were up-regulated upon PI3K inhibition and showed reduced expression in the hypertrophic zone. Regulation of these genes by PI3K signaling was confirmed by quantitative RT-PCR. We focused on F13a1 as an interesting target because of its known role in chondrocyte hypertrophy and osteoarthritis. Mouse E15.5 tibiae cultured with LY294002 (PI3K inhibitor) for 6 days showed decreased expression of factor XIIIa in the hypertrophic zone compared to control cultures. Discovering targets of signaling pathways in hypertrophic chondrocytes could lead to targeted therapy in osteoarthritis and a better understanding of the cartilage environment for tissue engineering.


The myocardin-related transcription factor, MASTR, cooperates with MyoD to activate skeletal muscle gene expression.
The myocardin family proteins (myocardin, MRTF-A, and MRTF-B) are serum response factor (SRF) cofactors and potent transcription activators. Gene-ablation studies have indicated important developmental functions for myocardin family proteins primarily in regulation of cardiac and smooth muscle development. Using Xenopus genome and cDNA databases, we identified a myocardin-related transcription factor expressed specifically in the skeletal muscle lineage. Synteny and sequence alignments indicate that this gene is the frog orthologue of mouse MASTR [Creemers EE, Sutherland LB, Oh J, Barbosa AC, Olson EN (2006) Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR. Mol Cell 23:83-96]. Inhibition of MASTR function in the Xenopus embryo by using dominant-negative constructions or morpholino knockdown results in a dramatic reduction in expression of skeletal muscle marker genes. Overexpression of MASTR in whole embryos or embryonic tissue explants induces ectopic expression of muscle marker genes. Furthermore, MASTR cooperates with the myogenic regulatory factors MyoD and Myf5 to activate transcription of skeletal muscle genes. An essential function for MASTR in regulation of myogenic development in the vertebrate embryo has not been previously indicated.


Exploring the relationship between preferences for high fat foods and efficacy of the ketogenic and modified Atkins diets among children with seizure disorders.
Previous research has indicated that children with seizures may prefer high fat foods - a preference compatible with ketogenic and modified Atkins dietary therapies. The purpose of this prospective study was to examine the relationship between fat preference and efficacy of therapeutic diets in treating intractable seizures among a pediatric population. Preference for high fat foods was directly assessed in a sample of 30 children prior to commencing either the ketogenic or modified Atkins diet. Seizure control was assessed at 1, 3, 6, and 12 months following diet initiation. Using an intent-to-treat analysis, correlations between fat preference and diet efficacy were examined at each follow-up and across the follow-up period. At individual follow-ups, correlations between fat preference and diet efficacy varied in terms of both strength and significance; however, modest, positive correlations with fat preference were significant when examining high levels of efficacy (100% seizure reduction, ≥90% seizure reduction) across a 1-year follow-up period. These findings provide preliminary evidence that fat preference, when directly assessed, may be a useful predictor of treatment efficacy for the ketogenic and modified Atkins diets; however, further research is necessary.


To walk or to fly? How birds choose among foraging modes.
We test the predictive value of the main energetic currencies used in foraging theory using starlings that choose between two foraging modes (walking versus flying). Walking is low-cost, low-yield, whereas flying is the opposite. We fixed experimentally, at 11 different values, the amount of flight required to get one food reward, and for each flight cost value, we titrated the amount of walking until the birds showed indifference between foraging modes. We then compared the indifference points to those predicted by gross rate of gain over time, net rate of gain over time, and the ratio of gain to expenditure (efficiency). The results for the choice between modes show strong qualitative and quantitative support for net rate of gain over time over the alternatives. However, the birds foraged for only a fraction of the available time, indicating that the choice between foraging and resting could not be explained by any of these currencies. We suggest that this discrepancy could be accounted for functionally because nonenergetic factors such as predation risk may differ between resting and foraging in any mode but may not differ much between foraging modes, hence releasing the choice between foraging modes from the influence of such factors. Alternatively, the discrepancy may be attributable to the use of predictable (rather than stochastic) ratios of effort per prey in our experiment, and it may thus be better understood with mechanistic rather than functional arguments.


Prosthetic Valve Thrombosis: Diagnosis and Management.
St. Jude mechanical prosthesis is the most commonly used prosthetic device with least valvular complications with excellent hemodynamics. However, prosthetic valve thrombosis is one of the serious complications, with rates between 0.03% and 0.13% per patient-year depending on the type of anticoagulation used and compliance to the therapy. Transthoracic echocardiography (TTE) is the initial screening tool (class I) that would provide clues for the assessment of valvular hemodynamics. Fluoroscopy is an alternate imaging modality for the assessment of mechanical leaflet motion, especially in patients when prosthetic valves are difficult to image on TTE or transesophageal echocardiography. A complete fluoroscopic evaluation of a prosthetic valve includes assessment of valvular motion and structural integrity. Opening and closing angles can be measured fluoroscopically to determine whether a specific valve is functioning properly. We discuss a case of a 91-year-old man with thrombosis of bileaflet mechanical mitral prosthesis that was demonstrated on real-time fluoroscopy (not evident on TTE). An algorithmic approach to diagnosis and management of prosthetic heart valve thrombosis is outlined.


The positive impact of a facilitated peer mentoring program on academic skills of women faculty.
In academic medicine, women physicians lag behind their male counterparts in advancement and promotion to leadership positions. Lack of mentoring, among other factors, has been reported to contribute to this disparity. Peer mentoring has been reported as a successful alternative to the dyadic mentoring model for women interested in improving their academic productivity. We describe a facilitated peer mentoring program in our institution's department of medicine. Nineteen women enrolled in the program were divided into 5 groups. Each group had an assigned facilitator. Members of the respective groups met together with their facilitators at regular intervals during the 12 months of the project. A pre- and post-program evaluation consisting of a 25-item self-assessment of academic skills, self-efficacy, and academic career satisfaction was administered to each participant. At the end of 12 months, a total of 9 manuscripts were submitted to peer-reviewed journals, 6 of which are in press or have been published, and another 2 of which have been invited to be revised and resubmitted. At the end of the program, participants reported an increase in their satisfaction with academic achievement (mean score increase, 2.32 to 3.63; P = 0.0001), improvement in skills necessary to effectively search the medical literature (mean score increase, 3.32 to 4.05; P = 0.0009), an improvement in their ability to write a comprehensive review article (mean score increase, 2.89 to 3.63; P = 0.0017), and an improvement in their ability to critically evaluate the medical literature (mean score increased from 3.11 to 3.89; P = 0.0008). This facilitated peer mentoring program demonstrated a positive impact on the academic skills and manuscript writing for junior women faculty. This 1-year program required minimal institutional resources, and suggests a need for further study of this and other mentoring programs for women faculty.


Evaluation of a brief pilot psychoeducational support group intervention for family caregivers of cancer patients: a quasi-experimental mixed-methods study.
Family caregivers of cancer patients often experience an impaired quality of life (QOL) and emotional distress as a result of their caregiving duties, which may potentially influence the quality of care of their care recipients. The COPE (Caregivers of cancer Outpatients' Psycho-Education support group therapy) intervention was developed as a response to the lack of work done among family caregivers of ambulatory cancer patients in Asia. This group intervention comprised four weekly sessions simultaneously targeting psychoeducation, skills training, and supportive therapy. The present study sought to evaluate the pilot COPE intervention using both quantitative and qualitative measures. The Hospital Anxiety and Depression Scale (HADS) was used to measure both depression and anxiety, while the Caregiver QOL - Cancer (CQOLC) measured caregiver QOL. These instruments were measured at baseline pre-intervention, and immediately post-intervention. A waitlist control group design was adopted. A subset of caregivers from the intervention group were invited for a semi-structured interview post-intervention. Quantitative analyses suggest that while QOL remained stable in control group participants, intervention group participants experienced QOL improvements - both in overall QOL and in the specific domain of burden. There were no significant differences in the trajectories of depression and anxiety in both groups. Qualitative analyses suggest that this might have been a result of the intervention not only equipping participants with the relevant coping skills, but also providing a platform for emotional expression and situational reappraisal. The COPE intervention has shown some efficacy in helping family caregivers of cancer patients, but more work is required before this can be implemented. Current Controlled Trials NCT02120183 . Registered 17 April 2014. Retrospectively registered.


The cost-effectiveness of antenatal malaria prevention in sub-Saharan Africa.
Antimalarial chemoprophylaxis during pregnancy significantly increases the birth weight of babies born to primigravidae, but coverage in sub-Saharan Africa is very limited. This analysis assessed whether increasing coverage is justified on cost-effectiveness grounds. A standardized modeling framework was used to estimate ranges for the cost per discounted year of life lost averted by weekly chloroquine chemoprophylaxis and intermittent sulfadoxine-pyrimethamine (SP) treatment for primigravidae in an operational setting with moderate to high malaria transmission. The SP regimen was found to be more cost-effective than the chloroquine regimen, because of both lower costs and higher compliance. Both regimens appear to be a good value for money in comparison with other methods of malaria control and based on rough cost-effectiveness guidelines for low-income countries, even with high levels of drug resistance. However, extending the SP regimen to all gravidae and increasing the number of doses per pregnancy could make the intervention significantly less cost-effective.


Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials.
CPAP reduces blood pressure (BP) in patients with symptomatic obstructive sleep apnoea (OSA). Whether the same benefit is present in patients with minimally symptomatic OSA is unclear, thus a meta-analysis of existing trial data is required. The electronic databases Medline, Embase and trial registries were searched. Trials were eligible if they included patients with minimally symptomatic OSA, had randomised them to receive CPAP or either sham-CPAP or no CPAP, and recorded BP at baseline and follow-up. Individual participant data were obtained. Primary outcomes were absolute change in systolic and diastolic BP. Five eligible trials were found (1219 patients) from which data from four studies (1206 patients) were obtained. Mean (SD) baseline systolic and diastolic BP across all four studies was 131.2 (15.8) mm Hg and 80.9 (10.4) mm Hg, respectively. There was a slight increase in systolic BP of 1.1 mm Hg (95% CI -0.2 to 2.3, p=0.086) and a slight reduction in diastolic BP of 0.8 mm Hg (95% CI -1.6 to 0.1, p=0.083), although the results were not statistically significant. There was some evidence of an increase in systolic BP in patients using CPAP <4 h/night (1.5 mm Hg, 95% CI -0.0 to 3.1, p=0.052) and reduction in diastolic BP in patients using CPAP >4 h/night (-1.4 mm Hg, 95% CI -2.5 to -0.4, p=0.008). CPAP treatment reduced both subjective sleepiness (p<0.001) and OSA severity (p<0.001). Although CPAP treatment reduces OSA severity and sleepiness, it seems not to have a beneficial effect on BP in patients with minimally symptomatic OSA, except in patients who used CPAP for >4 h/night.


Cell migration that orients the dorsoventral axis is coordinated with anteroposterior patterning mediated by Hedgehog signaling in the early spider embryo.
The early embryo of the spider Achaearanea tepidariorum is emerging as a model for the simultaneous study of cell migration and pattern formation. A cell cluster internalized at the center of the radially symmetric germ disc expresses the evolutionarily conserved dorsal signal Decapentaplegic. This cell cluster migrates away from the germ disc center along the basal side of the epithelium to the germ disc rim. This cell migration is thought to be the symmetry-breaking event that establishes the orientation of the dorsoventral axis. In this study, knockdown of a patched homolog, At-ptc, that encodes a putative negative regulator of Hedgehog (Hh) signaling, prevented initiation of the symmetry-breaking cell migration. Knockdown of a smoothened homolog, At-smo, showed that Hh signaling inactivation also arrested the cells at the germ disc center, whereas moderate inactivation resulted in sporadic failure of cell migration termination at the germ disc rim. hh transcript expression patterns indicated that the rim and outside of the germ disc were the source of the Hh ligand. Analyses of patterning events suggested that in the germ disc, short-range Hh signal promotes anterior specification and long-range Hh signal represses caudal specification. Moreover, negative regulation of Hh signaling by At-ptc appears to be required for progressive derepression of caudal specification from the germ disc center. Cell migration defects caused by At-ptc and At-smo knockdown correlated with patterning defects in the germ disc epithelium. We propose that the cell migration crucial for dorsoventral axis orientation in Achaearanea is coordinated with anteroposterior patterning mediated by Hh signaling.


Automated insulin dosing guidance to optimise insulin management in patients with type 2 diabetes: a multicentre, randomised controlled trial.
Insulin therapy is most effective if dosage titrations are done regularly and frequently, which is seldom practical for most clinicians, resulting in an insulin titration gap. The d-Nav Insulin Guidance System (Hygieia, Livonia, MI, USA) is a handheld device that is used to measure glucose, determine glucose patterns, and automatically determine the appropriate next insulin dose. We aimed to determine whether the combination of the d-Nav device and health-care professional support is superior to health-care professional support alone. In this multicentre, randomised, controlled study, we recruited patients from three diabetes centres in the USA (in Detroit MI; Minneapolis, MN; and Des Moines IA). Patients were eligible if they were aged 21-70 years, diagnosed with type 2 diabetes with a glycated haemoglobin (HbA1c) concentration of 7·5% or higher (≥58 mmol/mol) and 11% or lower (≤97 mmol/mol), and had been using the same insulin regimen for the previous 3 months. Exclusion criteria included body-mass index of 45 kg/m2 or higher; severe cardiac, hepatic, or renal impairment; and more than two severe hypoglycaemic events in the past year. Eligible participants were randomly assigned (1:1), with randomisation blocked within each site, to either d-Nav and health-care professional support (intervention group) or health-care professional support alone (control group). Both groups were contacted seven times (three face-to-face and four phone visits) during 6 months of follow-up. The primary objective was to compare average change in HbA1c from baseline to 6 months. Safety was assessed by the frequency of hypoglycaemic events. The primary objective and safety were assessed in the intention-to-treat population. We used Student's t test to assess the primary outcome for statistical significance. This study was registered with ClinicalTrials.gov, number NCT02424500. Between Feb 2, 2015, and March 17, 2017, 236 patients were screened for eligibility, of whom 181 (77%) were enrolled and randomly assigned to the intervention (n=93) and control (n=88) groups. At baseline, mean HbA1c was 8·7% (SD 0·8; 72 mmol/mol [SD 8·8]) in the intervention group and 8·5% (SD 0·8; 69 mmol/mol [SD 8·8]) in the control group. The mean decrease in HbA1c from baseline to 6 months was 1·0% (SD 1·0; 11 mmol/mol [SD 11]) in the intervention group, and 0·3% (SD 0·9; 3·3 mmol/mol [9·9]) in the control group (p<0·0001). The frequency of hypoglycaemic events per month was similar between the groups (0·29 events per month [SD 0·48] in the intervention group vs 0·29 [SD 1·12] in the control group; p=0·96). The combination of automated insulin titration guidance with support from health-care professionals offers superior glycaemic control compared with support from health-care professionals alone. Such a solution facilitated safe and effective insulin titration in a large group of patients with type 2 diabetes, and now needs to be evaluated across large health-care systems to confirm these findings and study cost-effectiveness. US National Institutes of Health, National Institute of Digestive and Kidney Diseases.


Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.
Alteration to the expression and activity of androgen receptor (AR) coregulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR coregulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and colocated with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARV), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR coregulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also as a suppressor of metastasis-related phenotypes. Cancer Res; 77(13); 3417-30. ©2017 AACR.


Care of the dying doctor: on the other end of the stethoscope.
The challenges of caring for a dying doctor reflect both common issues in helping the terminally ill and unique problems in working with a physician-patient. The dying doctor must deal with a familiar environment and set of problems from a radically different perspective and must negotiate overlapping and conflicting personal and professional roles. Some of the cardinal virtues of physicians--professional identity, expertise, perfectionism, selflessness, and stoicism--may pose both strengths and liabilities in the patient's role. The treating physicians may also encounter new strains in caring for a colleague. They must guard against both overinvolvement and underinvolvement, and, as with all dying persons, they must serve as a guide through unfamiliar territory for dying patient and family--a companion who is not afraid to listen to or explore the most upsetting matters, a person who can speak frankly when others may be ignoring "the horse on the dining room table." The case of Dr B, an internist dying of myelofibrosis and congestive heart failure, whose son is also a physician, offers the reader the opportunity to reflect on these challenges and to draw lessons about how to best care for fellow physicians at a time of great need. We suggest strategies for negotiating the patient-physician relationship when the patient is also a physician.


Anti-Oppressive Practice and Reflexive Lifeworld-Led Approaches to Care: A Framework for Teaching Nurses about Social Justice.
This paper was initially written for a European Academy of Caring Science workshop and aimed to provide clarity and direction about Caring Science by offering some ideas emerging from the philosophy, themes, and projects of EACS. An underpinning concept for the work of the Academy is the lifeworld. The focus of the workshop was to explore the lifeworld of the patient, student, and carer. The intention was to promote discussion around the need to provide alternative ways to conceptualise caring relevant knowledge, naming phenomena and practices central to caring sciences, and the educational curriculum and its adequacy for caring science. This paper seeks to identify concepts and approaches to understanding oppression, power, and justice which enable nurses to challenge the structures in health care environments which discriminate or disempower clients. Anti-oppressive practice theory and reflexive lifeworld-led approaches to care enable nurses to be critical of their practice. A framework for teaching social justice in health care is offered to augment teaching students to challenge oppressive practice and to assist nurses to reflect and develop conceptual models to guide practices which are central to promoting caring interactions.


An uncertain role for p53 gene alterations in human prostate cancers.
Inactivation of the p53 gene has been implicated in prostate cancer progression. To determine the role of p53 inactivation in the progression of clinical prostatic carcinomas, we assessed 67 tumors derived from patients with clinically localized disease for chromosome 17p and p53 gene allelic loss, p53 gene mutations using single-strand conformational polymorphism and direct sequencing, and p53 protein expression using immunohistochemical staining. Of 55 informative tumors, 10 demonstrated loss of 17p or the p53 gene; however, only a single tumor had a mutation in its remaining p53 allele. Significant p53 overexpression was observed in 2 of 38 tumors, and 9 others had faint staining of a few nuclei ( < 1%). p53 overexpression occurred in no informative tumor with allelic loss or mutation. In a 1-7-year follow-up, positive immunohistochemical staining did not confer an increased risk of recurrence (risk of recurrence, 0.86, P = 0.78), whereas allelic loss of chromosome 17p appeared to be highly correlated with recurrence (risk of recurrence, 3.7, P = 0.003). In an unrelated group of 42 patients with metastatic prostate cancer, p53 overexpression was found in 26 tumors (62%), and 15(36%) had high grade staining. Neither the presence nor the degree of expression correlated with time to progression or time to death. This series suggests that p53 gene inactivation is rare in primary prostatic tumors, not essential to the development of prostate cancer metastases, and of limited use as a prognostic marker in patients with primary or metastatic disease. Another gene or genes on chromosome 17p may be involved in prostate cancer progression.


Awareness of risk factors for cancer among British adults.
Awareness of risk factors for five common cancers was assessed in a representative sample of 3 693 adults in the UK. Respondents were presented with a risk of 14 factors comprising 10 which have established links with various cancers (older age, many sexual partners, low fibre diet, smoking, a relative with the cancer, low fruit and vegetable diet, taking HRT/the contraceptive pill, being overweight, viruses or infection, and a high fat diet) and four so-called "mythic" causes (food additives, overhead power lines, pollution, stress). Out of 15 well-established associations between risk factors and cancers, the average number correctly identified was 5. Women and those with higher levels of education got more correct. Endorsement of mythic causes was comparatively low (less than 5% for most cancers), but were higher in men and those with less education. These results are somewhat reassuring in relation to the prevalence of erroneous beliefs, but raise considerable concern about public understanding of well established causes. Better health education will be needed to maximise public awareness of cancer prevention.


Winter-time climatic control on dissolved organic carbon export and surface water chemistry in an Adirondack forested watershed.
Although most of forested watersheds in temperate and boreal regions are snow-covered for a substantial portion of the year, responses of biogeochemical processes under the snow pack to climatic fluctuations are poorly understood. We investigated responses of dissolved organic carbon (DOC) and surface water chemistry in stream and lake discharge waters draining the Arbutus Lake Watershed in the Adirondacks of New York State to climatic fluctuations during the snow-covered months from December through April. Interannual variability in stream discharge corresponded to changes in air temperature and snow pack depth across the winter months. Concentrations of DOC in stream water draining a subcatchment showed immediate positive responses to rising temperatures and subsequent increases in runoff during most snowmelt events. Increases in DOC concentrations usually coincided with decreases in pH and increases in total aluminum (Al) concentrations, while the correlations between concentrations of DOC and SO4(2-) or base cations were negative. Although changes in air temperature, snow pack depth, and runoff were all significantly correlated with stream water concentrations of major solutes, stepwise linear regression found that runoff was the best predictor of solute concentrations. Results of stepwise linear regression with long-term monthly monitoring data collected at the lake outlet showed weaker but still consistent climatic effects on interannual variations in concentrations of DOC and other solutes. Over the 17 winter periods from December 1983 through April 2000, changes in seasonal average concentrations of DOC, H+, and Al in lake discharge generally corresponded to interannual variations in temperature, precipitation, and runoff, while SO4(2-) and base cations displayed an opposite trend. The results suggest that snowmelt-mediated DOC responses to temperature fluctuations during the winter months might offset increases in the surface water pH caused by decreasing acidic deposition and pose a potential hazard of Al toxicity in surface waters.


Noninvasive ventilation and exercise tolerance in heart failure: A systematic review and meta-analysis.
Patients with heart failure (HF) usually develop exercise intolerance. In this context, noninvasive ventilation (NIV) can help to increase physical performance. To undertake a systematic review and meta-analysis of randomized controlled trials that evaluated the effects of NIV on exercise tolerance in patients with HF. Search Strategy: Articles were searched in the following databases: Physiotherapy Evidence Database (PEDro), Scientific Electronic Library Online (SciELO), and MEDLINE. Selection Criteria: This review included only randomized controlled trials involving patients with HF undergoing NIV, with or without other therapies, that used exercise tolerance as an outcome, verified by the distance travelled in the six-minute walk test (6MWT), VO2peak in the cardiopulmonary test, time spent in testing, and dyspnea. Data Collection And Analysis: The methodological quality of the studies was rated according to the PEDro scale. Data were pooled in fixed-effect meta-analysis whenever possible. Four studies were selected. A meta-analysis including 18 participants showed that the use of NIV prior to the 6MWT promoted increased distance, [mean difference 65.29 m (95% CI 38.80 to 91.78)]. The use of NIV prior to the 6MWT in patients with HF may promote increased distance. However, the limited number of studies may have compromised a more definitive conclusion on the subject.


Expression of Ferroptosis-Related Proteins Glutathione Peroxidase 4, Nuclear Factor Erythroid 2-Related Factor 2, and Solute Carrier Family 7 Member 11 in Gastric Cancer Patients.
The aim of this study was to investigate the expression of ferroptosis-related targets glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and solute carrier family 7 member 11 in gastric cancer and the correlation between their expression and the clinicopathological characteristics and prognosis of gastric cancer patients. Forty-two gastric cancer samples and paracancerous samples were included, and all cases were detected with glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and solute carrier family 7 member 11 by immunohistochemistry. Six gastric cancer cell lines and 1 normal gastric epithelial cell were stably cultured, and the expression of target genes of different cell lines was detected using western blot and polymerase chain reaction. Public data were downloaded from the database, and analyses were performed by software including Statistical Package for the Social Sciences and Prism. A high glutathione peroxidase 4 expression level was found in 7 (16.67%) cancer tissues and 0 (0.00%) paracancerous tissues (P = .012). Nuclear factor erythroid 2-related factor 2 was upregulated in 23 (54.76%) cancer tissues and 2 (4.76%) paracancerous tissues (P < .001). Solute carrier family 7 member 11 showed increased expression in 4 (9.52%) cancer tissues and 1 (2.38%) paracancerous tissue (P = .356). No significant association existed between their expression and the clinicopathological characteristics and prognosis of gastric cancer patients. Glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 expressions were higher in all 6 gastric cancer cell lines compared to normal gastric epithelial cells. Glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 expressions were significantly higher in gastric cancer, which may be potential biomarkers of gastric cancer.


Substrate discrimination by formamidopyrimidine-DNA glycosylase: a mutational analysis.
Formamidopyrimidine-DNA glycosylase (Fpg) is a primary participant in the repair of 8-oxoguanine, an abundant oxidative DNA lesion. Although the structure of Fpg has been established, amino acid residues that define damage recognition have not been identified. We have combined molecular dynamics and bioinformatics approaches to address this issue. Site-specific mutagenesis coupled with enzyme kinetics was used to test our predictions. On the basis of molecular dynamics simulations, Lys-217 was predicted to interact with the O8 of extrahelical 8-oxoguanine accommodated in the binding pocket. Consistent with our computational studies, mutation of Lys-217 selectively reduced the ability of Fpg to excise 8-oxoguanine from DNA. Dihydrouracil, also a substrate for Fpg, served as a nonspecific control. Other residues involved in damage recognition (His-89, Arg-108, and Arg-109) were identified by combined conservation/structure analysis. Arg-108, which forms two hydrogen bonds with cytosine in Fpg-DNA, is a major determinant of opposite-base specificity. Mutation of this residue reduced excision of 8-oxoguanine from thermally unstable mispairs with guanine or thymine, while excision from the stable cytosine and adenine base pairs was less affected. Mutation of His-89 selectively diminished the rate of excision of 8-oxoguanine, whereas mutation of Arg-109 nearly abolished binding of Fpg to damaged DNA. Taken together, these results suggest that His-89 and Arg-109 form part of a reading head, a structural feature used by the enzyme to scan DNA for damage. His-89 and Lys-217 help determine the specificity of Fpg in recognizing the oxidatively damaged base, while Arg-108 provides specificity for bases positioned opposite the lesion.


Acute pancreatitis and concomitant use of pancreatitis-associated drugs.
Drug-induced pancreatitis (DIP) is considered a relative rare disease entity, perhaps due to lack of recognition. The objective of this study was to evaluate the prevalence of pancreatitis-associated drugs in a Dutch cohort of patients admitted for acute pancreatitis (AP) and to identify the proportion AP possibly attributable to the use of drugs. This was a multicenter observational study (EARL study). Etiology, disease course, use of pancreatitis-associated drugs at hospital admittance, and discontinuation of these drugs were evaluated. Drugs were scored by means of an evidence-based DIP classification system. The first documented hospital admissions of 168 patients were analyzed. In all, 70 out of 168 (41.6%; 95% confidence interval (CI): 34.5-49.2%) patients used pancreatitis-associated drugs at admission. In 26.2% (44/168; 95% CI: 20.1-33.3%) of cases, at least one class I pancreatitis-associated drug was used. Possibly DIP was present in 12.5% (21/168; 95% CI: 8.3-18.4%); in less than half of these patients (9/21 or 42.9%; 95% CI: 24.5-63.5%), the prescribed drugs were actually discontinued, with no recurrence of AP later on. Among the remaining 12 patients without discontinuation of their drugs use and in absence of an alternative etiologic cause of AP, 8 patients used a class I pancreatitis-associated drug, representing 4.8% (8/168, 95% CI: 2.4-9.1%) of the total study population. In this series, a remarkably high percentage of patients who were admitted because of an attack of AP used pancreatitis-associated drugs. Physicians should be more aware of the possibility of DIP in patients with otherwise unexplained AP and act appropriately by discontinuation of the drug.


Type D personality and illness perceptions in myocardial infarction patients.
To determine the relationship between Type D personality (the tendency to experience negative emotions and to be socially inhibited) and illness beliefs in postmyocardial infarction (MI) patients. One hundred and ninety-two MI patients participated. Patients were assessed on demographic variables and completed the Type D Scale (DS14) and Brief Illness Perceptions Questionnaire one week post-MI. Multivariate analysis of variance revealed that Type D patients were significantly different from non-Type D patients on every illness perception dimension. Type D patients believe that their illness has significantly more serious consequences (P<.001), will last significantly longer (P<.001), will be significantly less controllable by them (P<.05) or through treatment (P<.001) compared to non-Type D patients, and experience significantly more symptoms that they attribute to their illness (P<.001). In addition, they are significantly more concerned about their illness (P<.05), experience significantly more emotions as a result (P<.001), and find their illness to be significantly less comprehensible compared to non-Type D individuals (P<.001). Type D individuals possess a distinct profile of illness beliefs, which may help explain the adverse effect of Type D on health outcomes following MI. Future research should evaluate intervention strategies to tackle illness perceptions in these high-risk patients.


Looking Back in Anger? Retirement and Unemployment Scarring.
Unemployment affects future working conditions and job security negatively, thus reducing life satisfaction after reemployment. These employment-related scars of unemployment should not matter anymore when a person has retired. Using German panel data, we analyze unemployed persons' transition into retirement to test whether unemployment leaves scars beyond working life and thus for reasons that are not employment-related. We find that involuntary unemployment between the last job and retirement causes a loss in life satisfaction after retirement. People who influenced or even initiated unemployment, by contrast, show no scarring. The scarring effect goes beyond what can be explained by the income loss originating from reduced pensions. It shows up independently of whether the unemployment spell directly before retirement was the only experience of unemployment in a person's career, or whether she had also experienced unemployment at earlier times. We do not find evidence that early retirement or involuntary retirement are the reasons why formerly unemployed retirees display unemployment scarring.


Hypoxia-induced changes in standing balance.
A few studies in the literature have reported postural changes with hypoxia, but none have quantified the magnitude of change. Further understanding of this condition could have implications for patients at risk for falls, individuals undergoing acute altitude exposure, and pilots and commercial passengers. The objective of this study was to evaluate the effect of different levels of hypoxia (oxygen nitrogen mixtures) on postural standing balance using the computerized dynamic posturography (CDP) system. This improves upon previous protocols by manipulating vision and standing balance with a sway-referenced visual field and/or platform. Additionally, normative data were available for comparison with the cumulative test scores and scores for each condition. Altitude hypoxia was simulated by use of admixing nitrogen to the breathing gas to achieve equivalent altitudes of 1524 m, 2438 m, and 3048 m. Subjects were evaluated using the CDP system. Subjects showed an overall trend toward decreased performance at higher simulated altitudes consistent with the initial hypothesis. Composite standing balance sway scores for the sensory organization subtest of CDP were decreased compared to baseline for simulated altitudes as low as 2438 m (mean sway scores: 81.92 at baseline; 81.85 at 1524 m; 79.15 at 2438 m; 79.15 at 3048 m). Reaction times to unexpected movements in the support surface for the motor control subtest (MCT) increased compared to baseline (mean composite scores: 133.3 at baseline; 135.9 ms at 1524 m; 138.0 ms at 2438 m; 140.9 ms at 3048 m). The CDP testing provided a reliable objective measurement of degradation of balance under hypoxic conditions.


Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro.
Cholangiocarcinoma (CC) is a primary liver cancer with increasing incidence worldwide. Despite all efforts made in past years, prognosis remains to be poor. At least in part, this might be explained by a pronounced resistance of CC cells to undergo apoptosis. Thus, new therapeutic strategies are imperatively required. In this study we investigated the effect of Salinomycin, a polyether ionophore antibiotic, on CC cells as an appropriate agent to treat CC. Salinomycin was quite recently identified to induce apoptosis in cancer stem cells and to overcome apoptosis-resistance in several leukemia-cells and other cancer cell lines of different origin. To delineate the effects of Salinomycin on CC, we established an in vitro cell culture model using three different human CC cell lines. After treatment apoptosis as well as migration and proliferation behavior was assessed and additional cell cycle analyses were performed by flowcytometry. By demonstrating Annexin V and TUNEL positivity of human CC cells, we provide evidence that Salinomycin reveals the capacity to break apoptosis-resistance in CC cells. Furthermore, we are able to demonstrate that the non-apoptotic cell fraction is characterized by sustainable impaired migration and proliferation. Cell cycle analyses revealed G2-phase accumulation of human CC cells after treatment with Salinomycin. Even though apoptosis is induced in two of three cell lines of CC cells, one cell line remained unaffected in regard of apoptosis but revealed as the other CC cells decreased proliferation and migration. In this study, we are able to demonstrate that Salinomycin is an effective agent against previously resistant CC cells and might be a potential candidate for the treatment of CC in the future.


Volume holographic hyperspectral imaging.
A volume hologram has two degenerate Bragg-phase-matching dimensions and provides the capability of volume holographic imaging. We demonstrate two volume holographic imaging architectures and investigate their imaging resolution, aberration, and sensitivity. The first architecture uses the hologram directly as an objective imaging element where strong aberration is observed and confirmed by simulation. The second architecture uses an imaging lens and a transmission geometry hologram to achieve linear two-dimensional optical sectioning and imaging of a four-dimensional (spatial plus spectral dimensions) object hyperspace. Multiplexed holograms can achieve simultaneously three-dimensional imaging of an object without a scanning mechanism.


Caring for women with ovarian cancer in the last year of life: a longitudinal study of caregiver quality of life, distress and unmet needs.
Caregiver burden, quality of life (QOL) and unmet needs are poorly understood, particularly at the end of life. We explored these issues in caregivers of women with ovarian cancer. The Australian Ovarian Cancer Study (AOCS) is a prospective population-based study of women newly diagnosed with primary epithelial ovarian cancer. Ninety-nine caregivers of women participating in the AOCS QOL sub-study (88% response rate) rated their QOL (SF-12), psychological distress (HADS), optimism (LOT), social support (Duke) and unmet needs (SCNS-carers), and patients rated their QOL (FACT-O), every three months for two years. This analysis included measurements in the patient's last year of life. Caregivers had significantly lower mental and physical QOL than population norms (p<0.01). Mean distress (p=0.01) and unmet needs increased over time, however social support remained constant. In linear mixed models, (using scores for each psychosocial variable over time), optimism (p<0.0001), social support (p<0.0001), higher unmet needs (p=0.008), physical wellbeing (p<0.0001), and time to death (p<0.0001) but not patient QOL, predicted caregiver mental well-being and distress. Highest unmet needs in the last 6months related to managing emotions about prognosis, fear of cancer spread, balancing one's own and the patient's needs, impact of caring on work and making decisions in the context of uncertainty. Aspects of caregiver functioning, rather than patient quality of life, predict caregiver quality of life and distress. Caregivers need help with managing emotions about prognosis, balancing their own and the patient's needs, work, and decision-making when there is uncertainty.


Diffuse epithelioid malignant mesothelioma of the pleura presenting as a hydropneumothorax and vertebral body invasion.
Malignant mesothelioma is an uncommon form of neoplastic transformation of the mesothelial cells that line the serosal surfaces of the body. It most commonly affects the pleura and is often associated with pleural effusions and pleural-based masses. The annual incidence in the United States is only 3300 cases, representing less than 0.3% of all cancers worldwide, although this is likely underestimated. We present a case of diffuse epithelioid malignant pleural mesothelioma in a patient with remote, short-term asbestos exposure complicated by recurrent left-sided hydropneumothoraces and pleural-based invasion of the T12 vertebral body, which represent two rare coexisting complications. This case illustrates the importance of maintaining a broad differential for hydropneumothorax, particularly as the risk factors may be decades removed and the degree of asbestos exposure to induce a malignant mesothelioma may be smaller than has been traditionally thought.


Hydrogels in acellular and cellular strategies for intervertebral disc regeneration.
Low back pain is an extremely common illness syndrome that causes patient suffering and disability and requires urgent solutions to improve the quality of life of these patients. Treatment options aimed to regenerate the intervertebral disc (IVD) are still under development. The cellular complexity of IVD, and consequently its fine regulatory system, makes it a challenge to the scientific community. Biomaterials-based therapies are the most interesting solutions to date, whereby tissue engineering and regenerative medicine (TE&RM) strategies are included. By using such strategies, i.e., combining biomaterials, cells, and biomolecules, the ultimate goal of reaching a complete integration between native and neo-tissue can be achieved. Hydrogels are promising materials for restoring IVD, mainly nucleus pulposus (NP). This study presents an overview of the use of hydrogels in acellular and cellular strategies for intervertebral disc regeneration. To better understand IVD and its functioning, this study will focus on several aspects: anatomy, pathophysiology, cellular and biomolecular performance, intrinsic healing processes, and current therapies. In addition, the application of hydrogels as NP substitutes will be addressed due to their similarities to NP mechanical properties and extracellular matrix. These hydrogels can be used in cellular strategies when combined with cells from different sources, or in acellular strategies by performing the functionalization of the hydrogels with biomolecules. In addition, a brief summary of therapies based on simple injection for primary biological repair will be examined. Finally, special emphasis will focus on reviewing original studies reporting on the use of autologous cells and biomolecules such as platelet-rich plasma and their potential clinical applications.


Prevalence of musculoskeletal disorders among cashew factory workers.
Work-related musculoskeletal disorders (WRMSDs) are impairments of the bodily structures, such as muscles, joints, tendons, ligaments, nerves, or the localized blood circulation system, which are caused or aggravated primarily by the performance of work and by the effects of the immediate environment in which work is carried out. Types of work in the cashew factory include cutting, peeling, grading, packing, and boiling. All these activities have risk factors for the musculoskeletal disorders, which include repetition, contact stress, forceful contraction, awkward postures, as well as sustained positions. The objective of this cross-sectional study was to find out the prevalence of musculoskeletal disorders among cashew factory workers. A cross-sectional descriptive study was conducted on 246 cashew factory workers, working in a randomly selected factory of a selected locality in Karkala taluk of Udupi district, Karnataka. Participants' name, age, gender, literacy level, income, type of work, duration of employment, hours of work per day, hand dominance, pain and discomfort status were obtained by structured interview. A total of 246 cashew factory workers participated in the study. Data were analyzed using SPSS version 14. Descriptive statistics was used to summarize the data. Around 28.5% (n = 70) reported pain, whereas 71.5% (n = 176) of workers did not report pain. The largest number of workers (n = 22; 32.4%) complained of pain in the knee, followed by back (n = 21; 30.9%) and then shoulder (n = 8; 11.8%). Seventy percent of the workers who reported pain were having more than 5 years of work experience. A 68.6% (n = 48) of the workers who reported pain were in the cutting category, followed by the grading (17%; n = 12), boiling (8.6%; n = 6), and peeling (5.7%; n = 4) categories. Prevalence of pain and discomfort among workers was 28.5%, which is a not ignorable and has to be addressed. Self-reported pain and discomfort were more prevalent in knee, followed by back and then shoulder.


Investigation of PMD in direct-detection optical OFDM with zero padding.
We investigate the polarization-mode dispersion (PMD) effect of zero padding OFDM (ZP-OFDM) in direct-detection optical orthogonal frequency division multiplexing (DDO-OFDM) systems. We first study the conventional equalization method for ZP-OFDM. Then an equalization method based on sorted QR decomposition is proposed to further improve the performance. It is found that the performance improvement of ZP-OFDM is due to the frequency domain oversampling (FDO) induced inter-carrier interference (ICI). Numerical simulation results show that compared with cyclic prefix OFDM (CP-OFDM), ZP-OFDM has a significantly higher tolerance to PMD in DDO-OFDM systems when the channel spectral nulls occur at certain differential group delay (DGD) values.


Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials.
Temporary dose modifications, such as reductions or interruptions, may allow patients to better manage adverse events (AEs) associated with pirfenidone use and continue treatment for idiopathic pulmonary fibrosis (IPF). However, the impact of such dosing adjustments on efficacy and safety is uncertain. Patients randomised to receive treatment with pirfenidone 2403 mg/day or placebo in the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY (Study 004 (NCT00287716)) and Study 006 (NCT00287729))) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND (Study 016 (NCT01366209)) trials were included in the analysis (n=1247). Descriptive statistics and a linear mixed-effects model (slope analysis) for annual rate of decline in forced vital capacity (FVC) by dose intensity were performed. Treatment-emergent AEs (TEAEs) were summarised and grouped by dose intensity or body size. Dose reductions and interruptions occurred in 76.9% (95% CI 73.4% to 80.1%) and 46.5% (95% CI 42.6% to 50.6%) of patients receiving pirfenidone vs 72.0% (95% CI 68.3% to 75.4%) and 31.1% (95% CI 27.5% to 34.9%) of patients receiving placebo, respectively. Dose interruptions tended to occur during the first 6 months of treatment, whereas dose reductions exhibited more variability. Less FVC decline from baseline was observed in patients receiving pirfenidone versus placebo at >90% dose intensity (p<0.001) or ≤90% dose intensity (p=0.0191), showing treatment benefit in both subgroups of dose intensity. No meaningful relationship between weight and TEAEs was observed. Dose interruptions, which may be required to manage TEAEs, mostly occurred during the first 6 months of treatment. Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on pirfenidone, without compromising its treatment effect compared with placebo. NCT00287729, NCT00287716, NCT01366209.