Dysregulation of NAD+ Metabolism Induces a Schwann Cell Dedifferentiation Program

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD⁺) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD⁺ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD⁺ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD⁺ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD⁺ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD⁺ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD⁺ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD⁺ metabolism could underlie neuropathies associated with diabetes and aging.

SIGNIFICANCE STATEMENT In this study, we showed that Schwann cell differentiation status is critically dependent on NAD⁺ homeostasis. Aberrant regulation of NAD⁺ biosynthesis via NAMPT deletion results in a blockade of Schwann cell maturation during development and severe peripheral neuropathy without significant axon loss. The phenotype can be rescued by supplementation with nicotinic acid; however, withdrawal of nicotinic acid leads to Schwann cell dedifferentiation, myelination defects, and death. These results provide new therapeutic possibilities for peripheral neuropathies associated with NAD⁺ decline during aging or diabetes.

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.

SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.

Distinct Populations of Motor Thalamic Neurons Encode Action Initiation, Action Selection, and Movement Vigor

Motor thalamus (Mthal) comprises the ventral anterior, ventral lateral, and ventral medial thalamic nuclei in rodents. This subcortical hub receives input from the basal ganglia (BG), cerebellum, and reticular thalamus in addition to connecting reciprocally with motor cortical regions. Despite the central location of Mthal, the mechanisms by which it influences movement remain unclear. To determine its role in generating ballistic, goal-directed movement, we recorded single-unit Mthal activity as male rats performed a two-alternative forced-choice task. A large population of Mthal neurons increased their firing briefly near movement initiation and could be segregated into functional groups based on their behavioral correlates. The activity of "initiation" units was more tightly locked to instructional cues than movement onset, did not predict which direction the rat would move, and was anticorrelated with reaction time (RT). Conversely, the activity of "execution" units was more tightly locked to movement onset than instructional cues, predicted which direction the rat would move, and was anticorrelated with both RT and movement time. These results suggest that Mthal influences choice RT performance in two stages: short latency, nonspecific action initiation followed by action selection/invigoration. We discuss the implications of these results for models of motor control incorporating BG and cerebellar circuits.

SIGNIFICANCE STATEMENT Motor thalamus (Mthal) is a central node linking subcortical and cortical motor circuits, though its precise role in motor control is unclear. Here, we define distinct populations of Mthal neurons that either encode movement initiation, or both action selection and movement vigor. These results have important implications for understanding how basal ganglia, cerebellar, and motor cortical signals are integrated. Such an understanding is critical to defining the pathophysiology of a range of BG- and cerebellum-linked movement disorders, as well as refining pharmacologic and neuromodulatory approaches to their treatment.

Stimulation of the Prefrontal Cortex Reduces Intentions to Commit Aggression: A Randomized, Double-Blind, Placebo-Controlled, Stratified, Parallel-Group Trial

Although prefrontal brain impairments are one of the best-replicated brain imaging findings in relation to aggression, little is known about the causal role of this brain region. This study tests whether stimulating the dorsolateral prefrontal cortex using transcranial direct current stimulation (tDCS) reduces the likelihood of engaging in aggressive acts, and the mechanism underlying this relationship. In a double-blind, stratified, placebo-controlled, parallel-group, randomized trial, 81 human adults (36 males, 45 females) were randomly assigned to an active (N = 39) or placebo (N = 42) condition, and then followed up 1 d after the experiment session. Intentions to commit aggressive acts and behavioral aggression were assessed using hypothetical vignettes and a behavioral task, respectively. The secondary outcome was the perception of the moral wrongfulness of the aggressive acts. Compared with the sham controls, participants who received anodal stimulation reported being less likely to commit physical and sexual assault (p < 0.01). They also judged aggressive acts as more morally wrong (p < 0.05). Perceptions of greater moral wrongfulness regarding the aggressive acts accounted for 31% of the total effect of tDCS on intentions to commit aggression. Results provide experimental evidence that increasing activity in the prefrontal cortex can reduce intentions to commit aggression and enhance perceptions of the moral wrongfulness of the aggressive acts. Findings shed light on the biological underpinnings of aggression and theoretically have the potential to inform future interventions for aggression and violence.

SIGNIFICANCE STATEMENT Aggressive behaviors pose significant public health risks. Understanding the etiology of aggression is paramount to violence reduction. Investigations of the neural basis of aggression have largely supported correlational, rather than causal, interpretations, and the mediating processes underlying the prefrontal–aggression relationship remain to be well elucidated. Through a double-blind, stratified, placebo-controlled, parallel-group, randomized trial, this study tested whether upregulation of the prefrontal cortex reduces the likelihood of engaging in aggression. Results provide experimental evidence that increasing prefrontal cortical activity can reduce intent to commit aggressive acts. They also shed light on moral judgment as one mechanism that may link prefrontal deficits to aggression and, in theory, have the potential to inform future approaches toward reducing aggression.

Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells

Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABA_B receptors (GABA_BRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABA_BR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABA_B receptor signaling into GABA_BR-mediated inhibition.

SIGNIFICANCE STATEMENT The dentate gyrus exhibits sparse neural activity that is essential for the computational function of pattern separation. Sparse activity is ascribed to strong local inhibitory circuits in combination with low intrinsic excitability of the principal neurons, the granule cells. Here we show that constitutive activity of G protein-coupled inwardly rectifying potassium channels (GIRKs) underlies to the hallmark low resting membrane potential and input resistance of mature dentate neurons. Adult-born neurons initially lack functional GIRK channels, with constitutive and phasic GABA_B receptor-mediated GIRK inhibition developing in tandem after several weeks of maturation. Our results reveal that GABA_B/GIRK activity is an important determinant of low excitability of mature dentate granule cells that may contribute to sparse DG activity in vivo.

Postsynaptic FMRP Regulates Synaptogenesis In Vivo in the Developing Cochlear Nucleus

A global loss of the fragile X mental retardation protein (FMRP; encoded by the Fmr1 gene) leads to sensory dysfunction and intellectual disabilities. One underlying mechanism of these phenotypes is structural and functional deficits in synapses. Here, we determined the autonomous function of postsynaptic FMRP in circuit formation, synaptogenesis, and synaptic maturation. In normal cochlea nucleus, presynaptic auditory axons form large axosomatic endbulb synapses on cell bodies of postsynaptic bushy neurons. In ovo electroporation of drug-inducible Fmr1-shRNA constructs produced a mosaicism of FMRP expression in chicken (either sex) bushy neurons, leading to reduced FMRP levels in transfected, but not neighboring nontransfected, neurons. Structural analyses revealed that postsynaptic FMRP reduction led to smaller size and abnormal morphology of individual presynaptic endbulbs at both early and later developmental stages. We further examined whether FMRP reduction affects dendritic development, as a potential mechanism underlying defective endbulb formation. Normally, chicken bushy neurons grow extensive dendrites at early stages and retract these dendrites when endbulbs begin to form. Neurons transfected with Fmr1 shRNA exhibited a remarkable delay in branch retraction, failing to provide necessary somatic surface for timely formation and growth of large endbulbs. Patch-clamp recording verified functional consequences of dendritic and synaptic deficits on neurotransmission, showing smaller amplitudes and slower kinetics of spontaneous and evoked EPSCs. Together, these data demonstrate that proper levels of postsynaptic FMRP are required for timely maturation of somatodendritic morphology, a delay of which may affect synaptogenesis and thus contribute to long-lasting deficits of excitatory synapses.

SIGNIFICANCE STATEMENT Fragile X mental retardation protein (FMRP) regulates a large variety of neuronal activities. A global loss of FMRP affects neural circuit development and synaptic function, leading to fragile X syndrome (FXS). Using temporally and spatially controlled genetic manipulations, this study provides the first in vivo report that autonomous FMRP regulates multiple stages of dendritic development, and that selective reduction of postsynaptic FMRP leads to abnormal development of excitatory presynaptic terminals and compromised neurotransmission. These observations demonstrate secondary influence of developmentally transient deficits in neuronal morphology and connectivity to the development of long-lasting synaptic pathology in FXS.

Pain-Related Expectation and Prediction Error Signals in the Anterior Insula Are Not Related to Aversiveness

The anterior insula has repeatedly been linked to the experience of aversive stimuli, such as pain. Previously, we showed that the anterior insula is involved in the integration of pain intensity and its prior expectation. However, it is unclear whether this integration occurs by a pain-specific expectation or a more general expectation of an aversive event. To dissociate these possibilities, we conducted an experiment using painful stimuli and aversive pictures with three levels of aversiveness on human male volunteers. Stimuli were preceded by a probabilistic, combined modality and intensity cue in a full factorial design. Subjective ratings of pain intensity and skin conductance responses were best explained by a combination of actual pain intensity and expected pain intensity. In addition, using fMRI, we investigated the neuronal implementation of the integration of prior expectation and pain intensity. Similar to subjective ratings and autonomic responses, the dorsal anterior insula represented pain intensity and expectations. The ventral anterior insula additionally represented the absolute difference of the two terms (i.e., the prediction error). The posterior insula only represented pain intensity. Importantly, the pattern observed in the anterior insula was only present if the cued modality was correct (i.e., expect pain); in case of an incorrect modality cue (i.e., expect aversive picture), the ventral anterior insula simply represented pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness.

SIGNIFICANCE STATEMENT The anterior insula has been shown to integrate pain intensity and their expectation. However, it is unclear whether this integration is pain-specific or related more generally to an aversive event. To address this, we combined painful stimuli and aversive pictures with three levels of aversiveness. The ventral anterior insula represented pain intensity, expectation, and their absolute difference (i.e., the prediction error). Importantly, this pattern was only observed if the cued modality was correct. In case of an incorrect modality cue, this area simply represented as pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness.

The State of the NIH BRAIN Initiative

The BRAIN Initiative arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.

Delving Deep into Crossmodal Integration

The Critical Role of the Hippocampus in Mind Wandering

Cellular Effects of Repetition Priming in the Aplysia Feeding Network Are Suppressed during a Task-Switch But Persist and Facilitate a Return to the Primed State

Many neural networks are multitasking and receive modulatory input, which configures activity. As a result, these networks can enter a relatively persistent state in which they are biased to generate one type of output as opposed to another. A question we address is as follows: what happens to this type of state when the network is forced to task-switch? We address this question in the feeding system of the mollusc Aplysia. This network generates ingestive and egestive motor programs. We focus on an identified neuron that is selectively active when programs are ingestive. Previous work has established that the increase in firing frequency observed during ingestive programs is at least partially mediated by an excitability increase. Here we identify the underlying cellular mechanism as the induction of a cAMP-dependent inward current. We ask how this current is impacted by the subsequent induction of egestive activity. Interestingly, we demonstrate that this task-switch does not eliminate the inward current but instead activates an outward current. The induction of the outward current obviously reduces the net inward current in the cell. This produces the decrease in excitability and firing frequency required for the task-switch. Importantly, however, the persistence of the inward current is not impacted. It remains present and coexists with the outward current. Consequently, when effects of egestive priming and the outward current dissipate, firing frequency and excitability remain above baseline levels. This presumably has important functional implications in that it will facilitate a return to ingestive activity.

SIGNIFICANCE STATEMENT Under physiological conditions, an animal generating a particular type of motor activity can be forced to at least briefly task-switch. In some circumstances, this involves the temporary induction of an "antagonistic" or incompatible motor program. For example, ingestion can be interrupted by a brief period of egestive activity. In this type of situation, it is often desirable for behavioral switching to occur rapidly and efficiently. In this report, we focus on a particular aspect of this type of task-switch. We determine how the priming that occurs when a multitasking network repeatedly generates one type of motor activity can be retained during the execution of an incompatible motor program.

This Week in The Journal

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage after Neurotrauma In Vivo

Loss of function following injury to the CNS is worsened by secondary degeneration of neurons and glia surrounding the injury and is initiated by oxidative damage. However, it is not yet known which cellular populations and structures are most vulnerable to oxidative damage in vivo. Using Nanoscale secondary ion mass spectrometry (NanoSIMS), oxidative damage was semiquantified within cellular subpopulations and structures of optic nerve vulnerable to secondary degeneration, following a partial transection of the optic nerve in adult female PVG rats. Simultaneous assessment of cellular subpopulations and structures revealed oligodendroglia as the most vulnerable to DNA oxidation following injury. 5-Ethynyl-2'-deoxyuridine (EdU) was used to label cells that proliferated in the first 3 d after injury. Injury led to increases in DNA, protein, and lipid damage in oligodendrocyte progenitor cells and mature oligodendrocytes at 3 d, regardless of proliferative state, associated with a decline in the numbers of oligodendrocyte progenitor cells at 7 d. O4⁺ preoligodendrocytes also exhibited increased lipid peroxidation. Interestingly, EdU⁺ mature oligodendrocytes derived after injury demonstrated increased early susceptibility to DNA damage and lipid peroxidation. However, EdU^– mature oligodendrocytes with high 8-hydroxyguanosine immunoreactivity were more likely to be caspase3⁺. By day 28, newly derived mature oligodendrocytes had significantly reduced myelin regulatory factor gene mRNA, indicating that the myelination potential of these cells may be reduced. The proportion of caspase3⁺ oligodendrocytes remained higher in EdU^– cells. Innovative use of NanoSIMS together with traditional immunohistochemistry and in situ hybridization have enabled the first demonstration of subpopulation specific oligodendroglial vulnerability to oxidative damage, due to secondary degeneration in vivo.

SIGNIFICANCE STATEMENT Injury to the CNS is characterized by oxidative damage in areas adjacent to the injury. However, the cellular subpopulations and structures most vulnerable to this damage remain to be elucidated. Here we use powerful NanoSIMS techniques to show increased oxidative damage in oligodendroglia and axons and to demonstrate that cells early in the oligodendroglial lineage are the most vulnerable to DNA oxidation. Further immunohistochemical and in situ hybridization investigation reveals that mature oligodendrocytes derived after injury are more vulnerable to oxidative damage than their counterparts existing at the time of injury and have reduced myelin regulatory factor gene mRNA, yet preexisting oligodendrocytes are more likely to die.

Papuloerythroderma of Ofuji successfully treated with methotrexate

Dermatologic Therapy, EarlyView.

Hyaluronic acid filler for skin rejuvenation: The role of diet on outcomes. A pilot study

Dermatologic Therapy, EarlyView.

Nitrogen and sulfur co-doped highly luminescent carbon dots for sensitive detection of Cd (II) ions and living cell imaging applications

Publication date: Available online 18 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Dan Gu, Liu Hong, Lei Zhang, Hao Liu, Shaoming Shang

Abstract

In this work, we have developed a green, simple and fast one-pot microwave-assisted strategy for synthesis of nitrogen and sulfur co-doped fluorescent carbon dots (CDs) using scallion (SL) as the carbon source. Optical properties of the SL-CDs have been measured by UV-visible and fluorescent spectroscopy. The morphology of the prepared SL-CDs has been performed by transmission electron microscopy (TEM). Surface functionality and elemental composition of SL-CDs was analyzed by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) spectra. The photoluminescent (PL) quantum yield of the obtained scallion carbon dots (SL-CDs) can reach as high as 18.6%. We further demonstrated that the SL-CDs can be used as fluorescent probes for detection of Cd²⁺ ions with a high sensitivity and an excellent selectivity. Linear relationships between the variation of the luminescent intensity of the SL-CDs before and after exposing the Cd²⁺ ions versus the concentration of Cd²⁺ ions in the range of 0.1–3.0 μM and 5.0–30.0 μM. The detection limit of Cd²⁺ ions can reach 15.0 nM. Moreover, the as-prepared SL-CDs exhibit negligible or extremely low cytotoxicity, which makes them be able to be used as fluorescent probes for living cell imaging. Overall, the prepared SL-CDs have promising applications in sensing of Cd²⁺ ions and in vivo or in vitro bioimaging.

Graphical Abstract

Sunscreen Use and Melanoma Risk Among Young Australian Adults

This population-based, case-control family study of data collected for the Australian Melanoma Family Study assesses the association of sunscreen use in childhood and early adulthood with the risk of cutaneous melanoma before age 40 years.

Spiky Skin in a Renal Transplant Recipient

A woman in her 70s with a cadaveric renal transplant presented with a 1-year history of a facial cutaneous eruption and mildly pruritic lesions, initially affecting malar cheeks and eyebrows and subsequently spreading to involve the nose, chin, upper trunk, and extremities. What is your diagnosis?

Timing of Onset of Adverse Cutaneous Reactions Associated With PD-1 Inhibitor Therapy

This observational study assesses the timing of onset of cutaneous reactions after initiation of programmed cell death protein 1 therapy in patients with metastatic melanoma or carcinoma.

A Comparison of Tanning Habits Among Gym Tanners and Other Tanners

This survey study evaluates the incidence of tanning in adults who use indoor gyms.

Effect of Stress Ball Use or Hand-holding on Anxiety During Skin Cancer Excision

This randomized clinical trial examines the effects of hand-holding vs stress ball use compared with usual care on anxiety in patients undergoing excisional removal of nonmelanoma skin cancer of the head or neck with local anesthesia.

Scabies—An Ancient Disease With Unanswered Questions in Modern Times

This Viewpoint discusses the global disease burden of scabies, as well as its diagnosis and treatment.

Predicting Fluoropyrimidine-Related Toxicity: Turning Wish to Will, The Pamm-Eortc Position

Inconsistent HIV reservoir dynamics and immune responses following anti-PD-1 therapy in cancer patients with HIV infection

Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study

Abstract

Background

Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation.

Patients and methods

This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received 3 cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m² cisplatin weekly during radiotherapy, which was delivered as 1.8–2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66–70 Gy to the involved neck. The primary endpoint was disease-free survival (DFS).

Results

In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm (5-year rate 61% vs 50%; hazard ratio = 0·739, 95% confidence interval (CI)= 0·565-0·965; P = 0·0264), after stratified for N3b and LDH, and adjusted for T stage.

Conclusion

Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved.

Clinical trial information

NCT00201396

Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment

Abstract

Background

In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anti-cancer agents or pro-apoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA).

Methods

We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated Salmonella typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models.

Results

INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expression. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). S. typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage.

Conclusion

Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high grade serous ovarian and squamous non-small cell lung cancer

Abstract

Background

We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.

Patients and Methods

In dose escalation, weekly paclitaxel (80 mg/m²) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.

Results

The dose escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. Based on toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m² paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28 - 18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%) and the mPFS was 5.8 months (95% CI: 2.76 - 21.25).

Discussion

In this phase I trial we report a highly active and well tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.

Clinical trial registration

ClinicialTrials.gov identifier: CNCT02193633

AJCC 8th Edition for Soft Tissue Sarcoma of the Extremities and Trunk

Novel therapies in urothelial carcinoma: a biomarker-driven approach

Abstract

Urothelial malignancies, including carcinomas of the bladder, ureters, and renal pelvis comprised approximately 8% of new cancer cases in the United States in 2016. In the metastatic setting, 15% of patients exhibit long-term survival following cisplatin-based chemotherapy and in patients with recurrent disease, response rates to second-line chemotherapy are generally 15-20% with a 3-month progression-free survival. However, recent advances in immunotherapy represent an opportunity to significantly improve patient outcomes. Moreover, the advent of next-generation sequencing (NGS) has resulted in both an improved understanding of the fundamental genetic changes that characterize urothelial carcinoma (UC) and identification of several candidate biomarkers of response to various therapies. Incorporation of prospective genotyping into clinical trials will allow for the identification and enrichment of patients most likely to respond to specific targeted therapies and chemotherapy. Combining different therapeutic classes to enhance outcomes is also an area of active research in UC.

Migraine and greater pain symptoms at 10-year follow-up among patients with major depressive disorder

No study has investigated the associations of migraine with pain symptoms over a ten-year period among outpatients with major depressive disorder (MDD). This study aimed to investigate this issue.

Vitamin D deficiency in patients with cluster headache: a preliminary study

Cluster headache is famous for attacks with seasonal and diurnal periodicity. This diurnal and seasonal variation might be related to sunlight and vitamin D metabolism. We investigated the serum vitamin D leve...

Increased thalamic glutamate/glutamine levels in migraineurs

Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexc...

Illuminating Endocrine Evolution: The Power and Potential of Large-Scale Comparative Analyses

Abstract

Hormones are central mediators of genotype-phenotype and organism-environment interactions. Despite these important functions, the role of selection in shaping hormonal mediators of phenotype remains poorly understood. Thanks to decades of work by endocrinologists, circulating hormone levels have been measured in a diversity of organisms. Variation in other endocrine traits and mediators (e.g., receptor expression, binding globulins), and the hormonal response to standardized challenges (e.g., restraint, pharmacological challenges) are also increasingly measured in both captive and free-living populations. Large-scale comparative analyses of the multitude of available endocrine data represent a particularly promising approach to addressing the function and evolution of these key phenotypic mediators, and their potential to serve as indicators of disturbance. Several recent phylogenetic comparative analyses and meta-analyses have begun to reveal the power and potential of these approaches to address key questions in integrative biology. Here we highlight two recent developments that are facilitating such analyses: increasingly powerful and flexible phylogenetic comparative methods, and the release of two endocrine trait databases – HormoneBase (currently 474 species) and the Wildlife Endocrinology Information Network (currently 25 species) – that contain compiled measures of endocrine traits across vertebrates. Increasingly comprehensive comparative analyses of endocrine data could provide insight into many interesting questions, including how rapidly changing environments are impacting phenotypes, why endocrine traits differ so remarkably within and across populations, and the evolution of plasticity.

Non-branching personal persistence

Abstract

Given reductionism about people, personal persistence must fundamentally consist in some kind of impersonal continuity relation. Typically, these continuity relations can hold from one to many. And, if they can, the analysis of personal persistence must include a non-branching clause to avoid non-transitive identities or multiple occupancy. It is far from obvious, however, what form this clause should take. This paper argues that previous accounts are inadequate and develops a new proposal.

2-hydroxyglutarate MR Spectroscopy for Prediction of Isocitrate Dehydrogenase Mutant Glioma: A Systemic Review and Meta-analysis using Individual Patient Data

Abstract

Background

Noninvasive and accurate modality to predict Isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. We aimed to investigate the diagnostic performance of 2-hydroxyglutarate (2HG) magnetic resonance spectroscopy (MRS) for prediction of IDH mutant glioma and provide an optimal cut-off value for 2HG.

Methods

A systematic literature search of Ovid-MEDLINE and EMBASE was performed to identify original articles investigating the diagnostic performance of 2HG MRS up to March 20, 2018. Pooled sensitivity and specificity were calculated using a bivariate random-effects model. Subgroup analysis and meta-regression was performed to explain heterogeneity effects. An optimal cut-off value for 2HG was calculated from studies providing individual patient data.

Results

Fourteen original articles with 460 patients were included. The pooled sensitivity and specificity for the diagnostic performance of 2HG MRS for prediction of IDH mutant glioma were 95% (95% CI, 85–98%) and 91% (95% CI, 83–96%), respectively. The Higgins I² statistic demonstrated that heterogeneity was present in the sensitivity (I² = 50.69%), but not in the specificity (I² = 30.37%). In the meta-regression, echo time (TE) was associated with study heterogeneity. Among the studies using point-resolved spectroscopy (PRESS), a long TE (97 ms) resulted in higher sensitivity (92%) and specificity (97%) than a short TE (30–35 ms; sensitivity of 90%, specificity of 88%; p < 0.01). The optimal 2HG cut-off value of 2HG using individual patient data was 1.76 mM.

Conclusion

2HG MRS demonstrated excellent specificity for prediction of IDH mutant glioma, with TE being associated with heterogeneity in the sensitivity.

Humean laws, explanatory circularity, and the aim of scientific explanation

Abstract

One of the main challenges confronting Humean accounts of natural law is that Humean laws appear to be unable to play the explanatory role of laws in scientific practice. The worry is roughly that if the laws are just regularities in the particular matters of fact (as the Humean would have it), then they cannot also explain the particular matters of fact, on pain of circularity. Loewer (Philoso Stud 160:115–137, 2012) has defended Humeanism, arguing that this worry only arises if we fail to distinguish between scientific and metaphysical explanations. However, Lange (Philoso Stud 165:255–261, 2013, Synthese 195:1337–1353, 2018) has argued that scientific and metaphysical explanations are linked by a transitivity principle, which would undercut Loewer's defense and re-ignite the circularity worry for the Humean. I argue here that the Humean has antecedent reasons to doubt that there are any systematic connections between scientific and metaphysical explanations. The reason is that the Humean should think that scientific and metaphysical explanation have disparate aims, and therefore that neither form of explanation is beholden to the other in its pronouncements about what explains what. Consequently, the Humean has every reason to doubt that Lange's transitivity principle obtains.

RECOTOX, a French initiative in ecotoxicology-toxicology to monitor, understand and mitigate the ecotoxicological impacts of pollutants in socioagroecosystems

Abstract

RECOTOX is a cross-cutting initiative promoting an integrated research to respond to the challenges of monitoring, understanding, and mitigating environmental and health impacts of pesticides in agroecosystems. The added value of RECOTOX is to develop a common culture around spatial ecotoxicology including the whole chain of pressure-exposure-impact, while strengthening an integrated network of in natura specifically equipped sites. In particular, it promotes transversal approaches at relevant socioecological system scales, to capitalize knowledge, expertise, and ongoing research in ecotoxicology and, to a lesser extent, environmental toxicology. Thus, it will open existing research infrastructures in environmental sciences to research programs in ecotoxicology of pesticides.

Hepatozelluläres Karzinom – Stellenwert von Resektion, Lebertransplantation und Immunsuppression

Zusammenfassung

Das hepatozelluläre Karzinom (HCC) kann im Stadium BCLC 0 und A (Barcelona Classification of Liver Cancer) sowohl mittels Resektion als auch mittels Lebertransplantation innerhalb der Mailand-Kriterien erfolgreich kurativ behandelt werden. Bei Patienten ohne Zirrhose sollte immer eine Resektion angestrebt werden. Problematisch bei der Beurteilung der Therapie mittels Resektion und Lebertransplantation ist die Vergleichbarkeit. Die Berücksichtigung der portalen Hypertension zur Indikationsstellung muss in der Risiko-Nutzen-Bewertung für die Resektion streng beachtet werden. Multiple Analysen zeigen, dass beide Verfahren zu ähnlichen Ergebnissen führen. Der Überlebensvorteil für die Transplantation ist allerdings erst nach 10 Jahren erreicht. Die Implementation der Werte für AFP (α-Fetoprotein) hilft bei der Risikoabschätzung. Bezüglich der immunsuppressiven Therapie scheint eine niedrig dosierte Langzeitimmunsuppression und die Gabe eines mTOR-Inhibitors (mTORi) positive Effekte auf das Langzeitüberleben zu haben.

Novel magnetic graphene oxide functionalized cyanopropyl nanocomposite as an adsorbent for the removal of Pb(II) ions from aqueous media: equilibrium and kinetic studies

Abstract

This work presents the synthesis of the novel silica-cyanopropyl functionalized magnetic graphene oxide (MGO/SiO₂-CN) hybrid nanomaterial derived by sol–gel method as a cheap efficient magnetic sorbent for the removal of extremely hazardous lead ions from aqueous media. The integration of the magnetic property, the carbon substrate, and the nitrile (–C ≡ N) containing organic grafted silica matrix promoted the adsorption capability against lead ions along with its simple synthesis recovery and low cost. The prepared nanocomposite was comprehensively characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Adsorption of lead was found to be pH dependent because of the charged nature of both analyte and adsorbent surface. Adsorption experiments were conducted under the optimum conditions, and the obtained experimental data from atomic absorption spectroscopy were analyzed using the popular isothermal models namely Langmuir, Freundlich, and Dubinin–Radushkevich isotherms as well as kinetically studied and evaluated for adsorption standard free energy (E). The experimental results have demonstrated the enhanced adsorption capability of the proposed sorbent nanocomposite for lead ion removal with the maximum adsorption capacity of 111.11 mg/g at pH 5.0. The proposed mechanism of lead adsorption was mainly attributed to the complexation of lead positive ions with the grafted –C ≡ N bond. The synergistic effect of the combination of three components (i.e., the magnetic graphene oxide matrix, the triple bond containing organic moiety, and the inorganic porous silica framework) excelled the adsorption capability and proved to be a good candidate as adsorbent for the removal of lead ions.

Study on the removal effect and influencing factors of nitrobenzene reduction by iron carbonate precipitates

Abstract

To investigate the activity of iron carbonate precipitates produced by long-term operation of Fe⁰ permeable reactive barriers, three kinds of precipitates, namely Fe₆(OH)₁₂CO₃, Fe₂(OH)₂CO₃, and FeCO₃, were prepared to reduce the pollutant nitrobenzene. We studied the reduction effects of these iron carbonate precipitates on nitrobenzene by considering three factors, namely the initial nitrobenzene concentration, initial pH, and precipitate dosage, and established the kinetic degradation using pseudo-first-order kinetics model. The results showed that all three precipitates can reduce nitrobenzene, and the order of reducing capability is Fe₆(OH)₁₂CO₃ > Fe₂(OH)₂CO₃ > FeCO₃; moreover, the removal efficiency values of nitrobenzene are 68.08, 53.00, and 50.29%. A high initial nitrobenzene concentration and high pH value are beneficial to nitrobenzene reduction, and removal efficiency was increased when pH was increased from 4 to 9. In addition, the increased precipitate addition in the Fe₆(OH)₁₂CO₃ and Fe₂(OH)₂CO₃ systems increased removal efficiency. Furthermore, the dosage did not significantly influence the removal rate in the FeCO₃ system. Fe₆(OH)₁₂CO₃ and Fe₂(OH)₂CO₃ mainly relied on the precipitate itself with the structural Fe(II) to reduce nitrobenzene, and FeCO₃ mainly relied on the dissolved Fe²⁺. The reaction of all three precipitates in reducing nitrobenzene followed the first-order reaction kinetics.

Nonvisualization of Sentinel Lymph Nodes by Lymphoscintigraphy in Primary Cutaneous Melanoma – Incidence, Risk Factors, and a Review of Management Options

PURPOSE: Lymphoscintigraphy (LS) is often obtained prior to sentinel lymph node biopsy (SLNB), especially in areas likely to have multiple or aberrant drainage patterns. This study aims to determine the incidence and characteristics of melanoma patients with a negative LS and to review the management options and surgical recommendations. METHODS: This is a retrospective study of patients with primary cutaneous melanoma who underwent SLNB between 2005 and 2016. Patients with nonvisualized lymph nodes on preoperative LS were compared in a 1:4 ratio with a randomly selected unmatched cohort drawn from all melanoma patients who underwent preoperative LS within the time period of the study. Demographic, clinical and outcome data were compared between these groups. RESULTS: A negative LS was seen in 2.3% of all cases (25 in 1073). In both univariate and multivariate analyses, predictive patient and tumor-specific factors for negative LS included older age and head and neck location. Patients with a non-visualized SLN had significantly worse overall survival compared with patients who had a visualized SLN, but there was no difference in melanoma-specific survival. In 16 of the 25 cases (64%), at least one SLN was found intraoperatively despite the negative LS. CONCLUSION: Older patients with head and neck melanomas are more likely to experience nodal nonvisualization on LS. In patients who have nodal nonvisualization, the surgeon should attempt SLNB at the time of excision of the primary lesion since a SLN can still be found in a majority of cases, and it offers prognostic information. CONFLICTS OF INTEREST AND SOURCE OF FUNDING: None of the authors have a financial interest in or a commercial association with any of the products, devices, or drugs mentioned in this manuscript. There was no source of funding for this manuscript. CORRESPONDING AUTHOR: Dr. Deepak Narayan, Yale University School of Medicine, Section of Plastic Surgery, 330 Cedar Street, P.O. Box 208041, New Haven, CT, 06520-8041, United States. Phone number: (203) 785-2570, Fax number: (203) 785-5714, deepak.narayan@yale.edu ©2018American Society of Plastic Surgeons

“Anatomic Basis of the Gastroepiploic Vascularized Lymph Node Transfer: A Radiographic Evaluation Using Computed Tomography Angiography (CTA)”

PURPOSE: The omentum, nourished by the gastroepiploic vessels, has gained popularity as an option for vascularized lymph node transfer (VLNT). The anatomy of the gastroepiploic vessels, omentum, and lymph nodes (LN) has not been investigated. The purpose of this study is to describe the right gastroepiploic artery (GEA) and related structures by using computed tomography angiography (CTA). MATERIALS AND METHODS: A retrospective analysis was conducted on 34 patients who received CTA. Statistical models were applied to identify right GEA and LN anatomical characteristics. RESULTS: The right GEA was identified in 33 of 34 patients. It was found to have a diameter of 2.49mm at its origin (SD 0.66). The gastroduodenal artery length prior to right GEA takeoff was 3.09cm (SD 1.31). Twenty-five patients had lymph nodes in the right GEA lymphosome. There were 2.7 LNs identified per patient (SD 2.12). The distance from the right GEA origin to the most proximal LN was 3.99cm (SD 2.21). The distance from the GEA origin to the third LN was 9.12cm (SD 5.06). Each LN was within 7.00mm (SD 6.2) of the right GEA. CONCLUSIONS: When using the right GEA donor site for VLNT, the plastic surgeon should anticipate using a pedicle length of 4cm, a total flap length of 9cm with 3cm of surrounding tissue in order to obtain at least 3 lymph nodes for transfer. CTA is an effective imaging modality that can be used for patient-specific surgical navigation prior to vascularized lymph node transfer. Financial Disclosure Statement: Ketan Patel is a consultant for Novadaq Corp and receives textbook royalties from Elsevier Corp. All other authors have no disclosures. Corresponding Author: Ketan M. Patel, M.D., Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, 1510 San Pablo Street, Suite 415, Los Angeles, CA 90033, ketan.patel@med.usc.edu ©2018American Society of Plastic Surgeons

Comparison of Pediatric Intercalary Allograft Reconstructions With and Without a Free Vascularized Fibula

Introduction: Lower extremity intercalary allograft reconstruction has traditionally been used to facilitate limb salvage. Combing the allograft with a vascularized fibula graft (FVFG) has been described; however there is a paucity of data comparing the outcome of these reconstructions. Material and Methods: 29 pediatric patients (15 males, 14 females) underwent lower extremity limb salvage with the use of intercalary cadaveric allograft at a mean age of 12 years. The most common diagnosis was osteosarcoma (n=18). Patients were reconstructed with an allograft alone (n=11) or supplemented with a FVFG (n=18). Results: The mean time to union of the allograft was 11 months, with 10 patients requiring additional bone grafting. There was no difference in the need for an additional bone graft (OR 0.87, P=1.0) between patients with a FVFG and those without. The allograft was revised in 3 patients due to fracture (n=2) and fracture and infection (n=1). In all these patients the allograft was not supplemented with a FVFG (P

Correlation between Quantity of Transferred Lymph Nodes and Outcome in Vascularized Submental Lymph Node Flap Transfer for Lower Limb Lymphedema

Background: Vascularized lymph node transfer (VLNT) has shown promising results in the treatment of lower limb lymphedema, but little is known about the number of lymph nodes needed for the transfer to achieve optimal results. This study investigated the correlation between number of transferred lymph nodes in submental VLNT and outcomes regarding limb circumference reduction and cellulitis incidence. Methods: Thirty-five patients who had received submental VLNT to an ankle for lower limb lymphedema, post-gynecological cancer treatment, were included in the study. Limb circumference was determined via tape measurement pre- and postoperatively and was used to calculate the circumferential difference. Ultrasonography was performed postoperatively to determine the number of lymph nodes within the transferred flap. Patients were divided into groups A-C depending on the number of transferred lymph nodes: 1-2 (n=10), 3-4 (n=14) and 5-8 (n=11), respectively. Results: The mean age was 60.0 ± 9.2 years. All flaps survived. The mean improvement of circumferential difference for the whole cohort was 19.8 ± 9.2 %. Groups B and C both had significantly higher improvements in the circumferential difference than group A (p=0.04 and p=0.02, respectively), but when compared to each other, the difference was non-significant. All groups had significant reductions in cellulitis incidence postoperatively. Conclusions: Submental VLNT for lower limb lymphedema reduced the incidence of cellulitis, regardless of the number of transferred lymph nodes. The transfer of 3 or more lymph nodes provided significantly better outcome regarding limb circumference reduction than the transfer of 2 or fewer lymph nodes. FINANCIAL DISCLOSURE STATEMENT: The authors have nothing to disclose. No funding was received for this article. AUTHOR CONTRIBUTIONS: JG and MHC were responsible for the study idea, design and follow-through. JG, SYC and WHC were responsible for data collection. All authors were involved in the interpretation of results. JG and MHC were responsible for statistical analysis. All authors were involved in critical review and approval of the final result. IRB NUMBER: 101-3481B ACKNOWLEDGMENTS: The authors would like to thank Miffy Chia-yu Lin, M. Sc., for her assistance in the preparation of tables and figures for this manuscript. CORRESPONDING AUTHOR: Ming-Huei Cheng, MD, MBA, FACS, Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Center of Tissue Engineering, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, No. 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan , Telephone: +886 3 281200 ext. 2172, Fax: +886 3 3972681, E-mail: minghueicheng@gmail.com, minghuei@adm.cgmh.org.tw ©2018American Society of Plastic Surgeons

Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution

No abstract available

Influence of Repaired Cleft Lip and Palate on Layperson Perception following Orthognathic Surgery

Background: Facial scarring and disharmony due to clefting is associated with psychosocial stress which may be improved by orthognathic surgery. The authors examine how a history of clefting influences change in layperson perception of a patient following orthognathic surgery. Methods: 1000 laypeople were recruited through Mechanical Turk to evaluate patient photographs pre- and post-orthognathic surgery. Nineteen patients – 5 with unilateral and 4 with bilateral clefting – were included. Respondents assessed 6 personality traits, 6 emotional expressions, and likelihood of 7 interpersonal experiences on a scale from 1-7. Results: Using Mann-Whitney U and independent samples t-tests, changes in all aspects of social perception post-procedure differed significantly between cleft vs. non-cleft cohorts (p

“Incidents of Mandibular Distraction Osteogenesis for Hemifacial Microsomia.”

Background: This article mainly focused on the safety and unexpected incidents of mandibular distraction osteogenesis in treating patients with hemifacial microsomia. Methods: Records of 71 patients with hemifacial microsomia treated by mandibular distraction osteogenesis from February 2010 to March 2015 were examined in this retrospective study. The modified mandibular osteotomy was conducted under the assistance of three-dimensional (3D) reconstruction, computer-aided design and rapid prototyping technique. Distraction was conducted 4-7 days postoperatively at a frequency of 1 mm/d; moreover, the distractor was kept in place for 4 to 13 months after the first operation before it was removed. The scope of distraction ranged from 20 to 40 mm. All incidents encountered during and following the mandibular distraction process were documented in the medical records of patients. The patients were followed up for an average of 34.4 months after the second-stage operation. Results: The overall rate of incidents was 36.6%. Of them, minor incidents, which could be resolved with or without noninvasive therapy, were observed in 18.3% of all procedures in this series. Meanwhile, the rate of moderate incidents necessitating invasive therapy was reported to be 12.7%, while that of major incidents that could not be resolved with invasive therapy was 5.6%. Conclusions: Mandibular distraction osteogenesis is a widely used procedure for treating patients with hemifacial microsomia. It is extremely important to be fully aware of variety of incidents occurring during and following the surgical procedure to minimize the incidence of such incidents. Financial Disclosure Statement: All authors has no financial conflict to disclose. The study was funder by Special Fund for Scientific Research in the Public Interest from National Health and Family Planning Commission of the People's Republic of China (No. 201502016), and 2015 Major Project of School/Institution of Plastic Surgery Hospital, Chinese Academic of Medical Sciences (No.Z2015008). Corresponding author: Zhiyong Shi, MD, Department of maxillofacial surgery, Plastic Surgery Hospital (Institude), Chinese Academy of Medical Sciences, Peking Union Medical College; No.33 Badachu Road, Shijingshan District, Beijing, 100144, China. zhangzy1011@163.com ©2018American Society of Plastic Surgeons

“Interposition Vein Grafting in Head and Neck Free Flap Reconstruction”

Background: Many surgeons are hesitant to use interposition vein grafting in head and neck microvascular free flap surgery due to concerns for elevated risk of flap loss. Methods: We conducted a review of patients who underwent head and neck free flap reconstruction between 2005 and 2015. The effect of vein grafts on flap compromise and flap loss were analyzed using univariate and multivariate models. Results: A total of 3240 free flaps were performed. Vein grafts were used in 241 flaps (7.4%). The free flap compromise rate was 14.5% with vein grafts and 3.4% without vein grafts (p

Long-term results in isolated metopic synostosis- the Oxford experience in 22 years.

Background: Metopic synostosis causing trigonocephaly is treated by fronto-orbital-advancement and remodelling to correct the deformity, cerebral distortion and to treat intracranial hypertension in a small number of cases. This study's aim was to evaluate complications, revisions and long-term outcomes. Methods: A retrospective chart review was performed on consecutive metopic craniosynostosis patients treated between February 1995 and February 2017 at the Oxford Craniofacial Unit. Results: 245 patients with isolated metopic synostosis were seen. 202 patients underwent fronto-orbital-advancement and remodelling. 50 (25%) female; 152 (75%) male. Mean age at surgery was 16.8 months. Mean weight preoperatively was 12kg. All patients received blood transfusion. Mean postoperative stay was 6 days. Average follow-up time was 8 years (range 0.5-22 years). There were 8 (4%) major complications. 6 (2.9%) patients required secondary calvarial-expansion for late raised intracranial pressure. 31 (15%) had other subsequent procedures including wire removal (8%) and forehead shape contouring (4%) with alloplastic onlay. Raised intracranial pressure prior to surgery was confirmed in 2 cases by intracranial pressure monitoring. Conclusion: Trigonocephaly is caused by metopic synostosis and is treated by fronto-orbital advancement and remodelling in order to restore both internal and external skull configuration. Following surgery, we identified a 2.9% risk of late raised intracranial pressure requiring a secondary calvarial-expansion, necessitating prolonged follow up in all cases. Temporal hollowing and forehead contour defects were not uncommon, resulting in a need for onlay recontouring in selected cases. This is the largest reported series of metopic synostosis. Financial disclosure statement: The authors have no financial disclosures. Presented at: 17th biennal congress of the International Society of Craniofacial Surgery (ISCFS), 24th-28th October 2017, Cancun, Mexico. Correspondence should be address to: Hamidreza Natghian M.D., Oxford Craniofacial Unit, Level LG1, West Wing, John Radcliffe Hospital, Headley Way, Headington, OX3 9DU, Oxford, United Kingdom. Email: Hamidreza.natghian@gmail.com ©2018American Society of Plastic Surgeons

“Targeted Muscle Reinnervation in the Lower Leg: An Anatomic Study.”

Introduction: Targeted muscle reinnervation (TMR) re-routes the ends of cut nerves to re-innervate small motor nerves of nearby muscles, with the goal of reducing neuroma pain and/or improving prosthesis function. Anatomical roadmaps for TMR have been established in the upper extremity and thigh, but not for the lower leg. Methods: The major branch points (MBPs) of motor nerves and the motor entry points (MEPs) to muscles of the leg were dissected in five cadaver specimens. Leg length was defined as distance from lateral femoral condyle to lateral malleolus. The distances from the lateral femoral condyle to MBPs and MEPs were recorded as a percentage of leg length to identify targets for TMR. Results: The tibialis anterior and extensor digitorum longus were both acceptable targets in the anterior compartment, with an average 4.4 MEPs within 10-80% and 3 MEPs within 20-80% leg length, respectively. The peroneus longus was the best target in the lateral compartment, with an average 5.8 MEPs within 20-70% leg length. The gastrocnemius and soleus were both acceptable targets in the superficial posterior compartment, with an average 4.4 MEPs within 0-40% and 6.2 MEPs within 20-80% leg length, respectively for each muscle. The flexor digitorum longus was the best target in the deep posterior compartment, with an average 6 MEPs within 30-90% leg length. Conclusions: TMR is technically feasible in the lower leg. This cadaveric study provides a roadmap for incision placement and identification of motor nerve targets. Financial Disclosure Statement: Dr. Ko is a speaker for Checkpoint Surgical, Cleveland OH. Dr. Dumanian is a speaker for Axogen, Inc. Alachua, FL. No funding was received for this article. Corresponding author: Gregory Dumanian, MD, ivision of Plastic Surgery, Northwestern Memorial Hospital, 675 N. St. Clair St, Suite19-250, Chicago, IL 60611 USA. email: gdumania@nm.org ©2018American Society of Plastic Surgeons

Sphenoid Dysplasia in Neurofibromatosis: Patterns of Presentation and Outcomes of Treatment

Introduction: Sphenoid wing dysplasia in patients with neurofibromatosis type 1 (NF-1) may result in challenging and significant changes, including ultimately vision loss. We describe the radiographic patterns of sphenoid dysmorphology with time and age, and the impact of surgical intervention on preservation of vision. Methods: A retrospective study was performed at a single pediatric hospital, identifying subjects with NF-1. Records were reviewed in their entirety for each subject, with attention to opthamalogic evaluation. Radiographic images were digitally analyzed and scored for sphenoid transformations on a grade of 0-3. Results: Fifty-two subjects were identified. On initial imaging, 42.31% had a normal sphenoid (grade 0), 32.69% had an abnormal contour (grade 1), 11.54% had thinning (grade 2), and 13.46% had a gross defect (grade 3). Among the 45 subjects with serial imaging, 55.56% demonstrated progression of the deformity of at least one grade. Deformity progression correlated with length of imaging interval. Enucleation was noted to occur more often in subjects with a gross sphenoid defect (p

Reply to Letter to the Editor by Dr. Innocenti et al. on our paper the Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution

No abstract available

The association between autologous breast reconstruction and body mass index in breast oncology

No abstract available

Reply: The association between autologous breast reconstruction and body mass index in breast oncology

No abstract available

Prepectoral Breast Reconstruction

No abstract available

Leaching of metals from asphalt pavement incorporating municipal solid waste incineration fly ash

Abstract

Rising municipal solid waste incineration (MSWI) makes it imperative to recycle the fly ash (FA). FA can be solidified by asphalt and then applied in the asphalt road. However, little information on the metal leaching and associated with risks from asphalt solidified forms for FA is available. In the present study, metal leaching characteristics and long-term leaching potential from the asphalt-based FA matrices was determined based on the national standard method and simulating the actual using of the solidified forms in highways, respectively. The immobilization effect of asphalt on MSWI FA is well. Leaching velocity was in the order of magnitude of 10^~10⁻⁶ cm h⁻¹ during the entire leaching period. At the early age, leaching velocity of metals is high, especially Zn, Cd, and Ba. Cumulative leaching concentration of metals and leaching time has positive correlation. Only considering the leaching of simulating acid, leaching of metals in asphalt-based matrices is very slow, and the leaching toxicity of metals is lower than the Chinese National Standard.

Rapid Onset of a Painful, Ulcerated Facial Lesion in a 58-Year-Old Woman

(See pages 478–9 for the Answer to the Photo Quiz.)

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Rapid Onset of a Painful, Ulcerated Facial Lesion in a 58-Year-Old Woman

(See page 477 for the Photo Quiz.)

Real-world cost-effectiveness of cetuximab in the third-line treatment of metastatic colorectal cancer based on patient chart review in the Netherlands

To assess the cost effectiveness of cetuximab in third-line treatment of patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) in routine clinical practice compared with best supportive care (BSC)...

Pilomatricome : corrélation dermatopathologie-dermatoscopie

Publication date: Available online 17 July 2018

Source: Annales de Dermatologie et de Vénéréologie

Author(s): P. Huet, G. Barnéon, B. Cribier

Fabrication of pure and moxifloxacin functionalized silver oxide nanoparticles for photocatalytic and antimicrobial activity

Publication date: Available online 17 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Sirajul Haq, Wajid Rehman, Muhammad Waseem, Vera Meynen, Saif Ullah Awan, Shaukat Saeed, Naseem Iqbal

Abstract

This paper reports the synthesis of silver oxide (Ag₂O) and moxifloxacin functionalized silver oxide (M-Ag₂O) nanoparticles for photocatalytic and antimicrobial activity. The Ag₂O nanoparticles were synthesized by using 2 dimethyl amino ethanol as reducing agent. The BET surface area measured from N₂ adsorption method was found to be 16.89 m²/g. The mix (cubic and hexagonal) phase of silver oxide (Ag₂O) nanoparticles was confirmed by X-rays diffraction (XRD). The extra diffracted peaks were observed after moxifloxacin fictionalization. The scanning electron micrographs display spherical shaped particles of different sizes. The elemental composition and weight percent of both samples were studied by energy dispersive X-ray (EDX). The decrease in the weight percent of silver with the subsequent increase in the weight percent of carbon and oxygen revealed the successful loading of moxifloxacin onto Ag₂O NPs. The two stages of weight loss due to the removal of physisorbed and chemisorbed water was examined during thermogravimetric analysis (TGA). The optical band gap derived from the diffuse reflectance spectrum (DRS) was 1.83 eV, which corresponds to the transmittance edge of 676 nm. The Fourier transform infrared (FTIR) band at 668.56 cm⁻¹ confirms the successful synthesis of moxifloxacin functionalized silver oxide (Ag₂O) nanoparticles. The pure Ag₂O nanoparticles were used for the degradation of rhodamine 6G and 98.56% dye was degraded in 330 min. The bacterial species selected for the present study were Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus Niger. Both pure and functionalized Ag₂O NPs were screened against selected bacterial and fungal species and they showed improved activity with the volume of samples taken in wells. However, the activity of Ag₂O NPs against fungi was found less effective than bacteria which may be due to the difference in the composition of the cell wall. Further gram-positive bacteria showed more resistance toward both samples as compared to the gram-negative bacteria. It was concluded that Ag₂O NPs upon conjugation with moxifloxacin displayed promising antimicrobial activity.

Less painful and effective intralesional injection method for lichen simplex chronicus

Publication date: Available online 17 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Han Mi Jung, Sung Hye Eun, Ji Hae Lee, Gyong Moon Kim, Jung Min Bae

Femoral artery ultrasound for improving the detection of atherosclerosis in psoriasis

Publication date: Available online 17 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Alvaro Gonzalez-Cantero, Jorge Gonzalez-Cantero, Ana Isabel Sanchez-Moya, Cristina Perez-Hortet, Salvador Arias-Santiago, Jose Luis Martin-Rodriguez, Cristina Schoendorff-Ortega, Jorge Luis Gonzalez-Calvin

Early Stage Melanoma and Hematopoietic Stem Cell Transplantation Outcomes

Publication date: Available online 17 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Charles J. Puza, Paul J. Mosca, Adela R. Cardones

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy

Publication date: Available online 17 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Jacob Siegel, Mariam Totonchy, William Damsky, Juliana Berk-Krauss, Frank Castiglione, Mario Sznol, Daniel P. Petrylak, Neal Fischbach, Sarah B. Goldberg, Roy H. Decker, Angeliki M. Stamatouli, Navid Hafez, Earl J. Glusac, Mary M. Tomayko, Jonathan S. Leventhal

Abstract

Background

Bullous disorders associated with anti-PD-1/PD-L1 therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established.

Objective

To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy.

Methods

We retrospectively reviewed the medical records of patients evaluated by the onco-dermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018.

Results

We identified 9 patients who developed bullous eruptions of 853 patients (∼1%) treated with anti-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression.

Limitations

This was a retrospective study from a single tertiary care center.

Conclusion

Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents.

Combination of paromomycin plus human anti-TNF-α antibodies to control the local inflammatory response in BALB/ mice with cutaneous leishmaniasis lesions

Cutaneous leishmaniasis (CL) is caused by a broad range of species of the genus Leishmania. In the skin lesions that appear following the phlebotomine bite, pro- and anti-inflammatory cytokines play different roles in resistance/susceptibility and determine the immunopathogenesis of Leishmania spp. infection [1]. Therefore, T helper 1 (Th1) inflammatory cytokines, especially interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-12, are crucial in the initiation of protective immunity against L.

Religion and the Plastic Surgeon: an Imam, a Minister, and a Rabbi Walk into a Surgical Centre

Abstract

Cultural competency has become a keystone in forming a successful doctor–patient relationship to provide culturally appropriate services that respect patients' ethno-cultural beliefs, values, attitudes, and conventions. In cosmetic surgery, an often-overlooked aspect of a patient's cultural is his and her religious beliefs. In response to this paucity of resources for cosmetic surgeons to enable them to properly service their religious patients, this project was undertaken. This review article covers the three main Abrahamic religions (Judaism, Christianity, and Islam) and was written with the assistance of a prominent bioethicist from each religion (see Acknowledgements). In discussing each religion, the article has been divided into two sections. The first section is a general overview of the religion's relationship with cosmetic surgery as summary provided by the consulting bioethicist. The second portion is an annotated review of additional resources providing the reader further details on that religion. For example, our bioethicists provide a general perspective on Christianity as a whole, and the annotated review focuses on differences between Catholics and Protestants. We recognize the heterogeneity that is inherent in religion and the cultural and geographic biases that affect it. However, we aim to provide the reader a broad and basic foundation of the relationship between Judaism, Christianity, and Islam with cosmetic surgery to begin to create common ground between the physician and the patient and improve the process of shared decision-making and thus our outcomes. This paper should be seen as a foundation to build upon rather than an authoritative source, and specific patient concerns should be addressed with the patient's own religious advisor.

Level of Evidence V

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Performance of ceria/iron oxide nano-composites based on chitosan as an effective adsorbent for removal of Cr(VI) and Co(II) ions from aqueous systems

Abstract

A novel chitosan/ceria/iron oxide (CS/ceria/Fe₃O₄) nano-composite adsorbent was synthesized for removal of Cr(VI) and Co(II) ions from aqueous systems in a batch system. The adsorbents were characterized by field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), thermal gravimetric analysis (TGA), and Brunauer- Emmett-Teller (BET) analyses. The behavior of swelling kinetics was also studied. The effect of several adsorption parameters including CeO₂ and Fe₃O₄ contents, initial pH, contact time, initial Cr(VI) and Co(II) concentration, and temperature on the adsorption capacity was studied. The double exponential model revealed a better fit with the kinetic data of Cr(VI) and Co(II) ions. The Cr(VI) and Co(II) adsorption process well fitted the Langmuir model. The maximum adsorption capacities estimated from Langmuir isotherm model were 315.4 and 260.6 mg/g for Cr(VI) and Co(II) ions, respectively. Also, thermodynamic parameters were used to distinguish the nature of Cr(VI) and Co(II) adsorption. The reusability of CS/ceria/Fe₃O₄ nano-composite was evaluated with stripping agents of 0.1 M NaOH and 0.1 M HNO₃. Finally, the evaluation of Cr(VI)-Co(II) coexisting system confirmed that the presence of Co(II) ions played an inhibitor role on the Cr(VI) adsorption.

A Randomized, Placebo-Controlled, Double-Blind, Prospective Clinical Trial of Botulinum Toxin Type A in Prevention of Hypertrophic Scar Development in Median Sternotomy Wound

Abstract

Background

Linear hypertrophic scar is a common surgical problem that can be difficult to manage, especially for the median sternotomy scar. Botulinum toxin type A (BTA) is widely used in cosmetic surgery and has been shown to improve scar quality recently. The aim of this study was to evaluate the efficacy of BTA injected in the early postoperative of median sternotomy on preventing scar formation.

Methods

In this prospective randomized controlled trial, 19 consecutive patients who underwent median sternotomy were enrolled. The median sternotomy wound in each patient was divided into the upper half and the lower half. Both halves of the wound were randomized to receive the treatment with either BTA or normal saline. At 6-month follow-up, scars were assessed using the Vancouver Scar Scale, scar widths were measured, and patients were asked to evaluate their overall satisfaction.

Results

Seventeen patients with median sternotomy wounds completed the entire study. At 6-month follow-up, the mean Vancouver Scar Scale score for the BTA-treated group was 3.44 ± 1.68 and for the normal saline control group was 6.29 ± 2.39, and there was a statistically significant difference between the two groups (P < 0.05). There were also significant improvements in scar width and patient satisfaction for the BTA-treated halves of the wounds (P < 0.05).

Conclusions

The study demonstrates that early postoperative BTA injection can decrease scar formation and reduce scar width in median sternotomy wounds, and the overall appearance is more satisfactory.

Level of Evidence I

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Systematic Review of Quality-of-Life Measurement After Aesthetic Rhinoplasty

Abstract

Introduction

The assessment of outcomes in aesthetic rhinoplasty is highly relevant because patient satisfaction and improved health-related quality of life (QoL) are the predominant factors in determining success. The patient-reported outcome measures (PROMs) employed in rhinoplasty research studies are remarkably diverse, thus yielding difficulties with data analysis. The aim of this article is to provide a comprehensive review of the literature to reveal the relevance of the QoL assessment for rhinosurgeons.

Methods

A systematic literature search with the terms "Rhinoplasty" and "Quality of Life" was conducted using PubMed/MEDLINE, Google Scholar and Cochrane databases. Primarily, all publications related to QoL following aesthetic rhinoplasty between 2002 and 2017 were identified. As a secondary selection, we focused on articles with a prospective study design, a significant cohort size (at least 50 patients) and a follow-up period of at least 6 months after aesthetic rhinoplasty.

Results

A total of 62 PROM studies assessing QoL following aesthetic rhinoplasties were obtained. We ascertained an increasing publication rate of QoL articles over the last 15 years. Only 17 studies satisfied comprehensive inclusion criteria of a high qualitative study selection. The Rhinoplasty Outcome Evaluation was the most frequently used QoL questionnaire of the secondary selection (70.6%). The total number of 16 various questionnaires exhibit high heterogeneity.

Conclusion

Our data strengthen the increasing importance of the assessment of QoL after rhinoplasty. Despite a lack of reliable publications with considerable heterogeneity and large variability in outcomes, functional-aesthetic rhinoplasty leads to a significant improvement of patient's health-related QoL.

Level of Evidence II

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Surfactants in the sea surface microlayer, subsurface water and fine marine aerosols in different background coastal areas

Abstract

This study aims to determine the concentrations of surfactants in the surface microlayer (SML), subsurface water (SSW) and fine mode aerosol (diameter size < 1.5 μm) at different coastal stations in Peninsular Malaysia. The concentrations of anionic and cationic surfactants were determined through colorimetric methods as methylene blue active substances (MBAS) and disulphine blue active substances (DBAS), respectively. Water-soluble ions, for the determination of fine mode aerosol sources, were determined using ion chromatography (IC) for anions (SO₄²⁻, NO₃⁻, Cl⁻ and F⁻) and cations (Na⁺, K⁺, Ca²⁺ and Mg²⁺). Principal component analysis (PCA), combined with multiple linear regression (MLR), was used to identify the possible sources of surfactants in fine aerosol. The results showed the concentrations of surfactants as MBAS and DBAS in the SML ranged between 0.23 ± 0.03 and 0.35 ± 0.01 μmol L⁻¹ and between 0.21 ± 0.02 and 0.29 ± 0.01 μmol L⁻¹, respectively. The enrichment factors (Efs) ratios between MBAS and DBAS in the SML and SSW ranged between 1.04 ± 0.01 and 1.32 ± 0.04, respectively. The station that is located near to tourism and industrial activities recorded the highest concentrations of surfactants in SML and SSW. The concentrations of surfactants in fine aerosol ranged between 62.29 and 106.57 pmol m⁻³. The three possible sources of fine aerosol during the northeast monsoon were aged sea spray/biomass burning (which accounted for 69% of the atmospheric aerosol), nitrate/mineral dust (23%) and sulphate/fresh sea salt (8%). During the southwest monsoon, the three main sources of atmospheric aerosol were biomass burning (71%), secondary inorganic aerosol (23%) and sea spray (6%). This study suggests anthropogenic sources are main contributors to the concentrations of surfactants in SML, SSW and fine aerosols.

Ecological and human health risk assessments in the context of soil heavy metal pollution in a typical industrial area of Shanghai, China

Abstract

The purpose of this study was to identify the concentrations, sources, and potential ecological and health risks of heavy metals in soils from a typical industrial area in Shanghai, China. A total of 28 surface soil samples were collected and analyzed for As, Cd, Cr, Cu, Pb, Ni, Zn, and Hg from the BAO steel industry in June and July 2016. Classic multivariate statistical and geostatistical analysis methods were used to detect the sources of heavy metals, and the ecological risk index (RI) and hazard index (HI) were calculated to assess the potential ecological and health risks. The results showed significant pollution levels, which were derived from the industrial production process and closely related to the spatial layout of the functional areas of the industry. The ecological risk assessment indicated that a very high concentration zone with values ranging from 2045 to 3417 mg kg⁻¹ represented considerable ecological risk in the range of 300 to 600. The main dominant factor affecting the ecological risk is toxicity rather than concentration. The health risk assessment indicated that noncarcinogenic risk was mainly caused by Cr, and the average HI value for adults was 6.48, while it was 39.01 for children. Thus, children face higher threats to heavy metals in soils. The average carcinogenic risk values for Ni, Cr, Cd, and As were 7.97E-09, 5.2E-07, 2.1E-10, and 2.1E-09, respectively, all of which were below the threshold values (1.0E − 04). These results provide basic information for the control and environmental management of heavy metal pollution in steel industrial regions.

Assessment, Truth and Religious Studies

Abstract

This paper addresses the question of what should determine whether students' answers to closed questions are marked as correct or incorrect in the context of formal religious education, and when their answers to open ended questions should be given more or less credit. Drawing on insights from Craig Bourne, Emily Caddick Bourne and Clare Jarmy, I argue that a combination of judged truth, and a range of well-argued cases about what ought to be believed given certain premises should constrain these assessment practices. Furthermore, I argue that if we cannot find any consistent, nonarbitrary account of how judgements of correctness and merit are in fact being made in the context of formal religious education, then this tells more against current practice's inconsistency and arbitrariness than against these constraints on how judgements of correctness and merit should be made.

The Relation Between the Lower Lateral Cartilages and the Function of the External Nasal Valve

Abstract

Introduction

The position of the lower lateral cartilages (LLC) is closely related to the function of the external nasal valve (ENV). When there is a cephalic malposition of these cartilages, the nasal alae have inadequate support, which leads to ENV insufficiency during deep inspiration.

Methods

Retrospective study with 60 patients evaluated: the positioning of the LLC and the occurrence of ENV insufficiency; the effectiveness of structuring the medial and lateral walls of the ENV; and the frequency of the grafts used for structuring it.

Results

Of the 60 operated cases, 37 patients (62%) had ENV insufficiency, in 23 cases there was cephalic malposition of the LLC, and in the latter group 17 patients (74%) presented this insufficiency. A structured ENV was effective in the treatment of this insufficiency (p = 0.001). A lateral crural strut graft was performed in 24 cases (40%) of 60 patients operated. The alar contour graft was performed from 2013 to 2015 in 4 patients (22%) of 18 cases operated, and between 2016 and 2018 it was performed in 29 patients (69%) out of 42 cases. The columellar strut was routinely used from 2013 to mid-2016 in 33 cases (100%), and after that period until the present day the tongue-in-groove technique was performed in 11 cases (41%) and in the remaining 16 cases (59%) the caudal septal extension graft was performed.

Conclusion

Cephalic malposition of the LLC is an important red flag of ENV insufficiency. This insufficiency should be treated by structuring the walls of the ENV.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Talking our way to systematicity

Abstract

Do we think in a language-like format? Taking the marker of language-like formats to be the property of unconstrained systematicity, this paper considers the following master argument for the claim that we do: (1) language is unconstrainedly systematic, (2) if language is unconstrainedly systematic then so is thought, (3) so thought is unconstrainedly systematic. It is easy to feel that there is something right about this argument, that there will be some way of filling in its details that will vindicate the idea that our thought must be unconstrainedly systematic given that the language in which we express it is. Clearly, however, the second premise needs support—we need a principled reason for moving from the unconstrained systematicity of language to the unconstrained systematicity of thought. This paper gives three passes at formulating such a principle. This turns out to be much harder than it might seem. We should, I conclude, resist falling too easily for the lure of this master argument for the language-like format of thought.

Investigation on spatiotemporal distribution of aerosol optical properties over two oceanic regions surrounding Indian subcontinent during summer monsoon season

Abstract

Columnar spectral aerosol optical depths (AODs) and total suspended particulate matter (TSPM) concentrations were collected on board the Oceanographic Research Vessel (ORV) of Sagar Kanya (SK) during 7–21 June 2014 (SK-313) and 31 July–14 August 2015 (SK-323) over the Arabian Sea (AS) and Bay of Bengal (BoB), respectively, for the two successive years during summer monsoon season. AOD measured at 500 nm (AOD₅₀₀) varied significantly from 0.08 to 0.66 (0.07 to 0.60), with a mean of 0.48 ± 0.13 (0.34 ± 0.13) over the BoB (AS) during SK-313 (SK-323). It simply implies that aerosol load was higher over BoB, not variability as the standard deviations of AOD over both oceans are identical (0.13). Daily AOD₅₀₀ ranged between 0.15 and 0.60 accounted for 70–75% of the total occurrences over two oceanic regions. Mean Ångström exponent (α or alpha) and Ångström turbidity coefficient (β or beta) were found to be 0.43 ± 0.17 (0.39 ± 0.19) and 0.37 ± 0.15 (0.27 ± 0.13), respectively, which are higher over the AS during SK-323 (SK-313) that indicate predominance of coarse-relative to fine-mode particles. On the other hand, the spectral curvature and second derivative of alpha (α′) also showed significant contribution of coarse-mode particles over fine during the two campaigns. Further, column aerosol size distribution (CSD) derived from the King's inversion also exhibited bimodal distribution with a predominant peak observed in the coarse mode (~1.0 μm) compared to the fine mode at a geometric mean radius at ~0.1 μm over two oceans. The observed data showed that the two marine regions are significantly influenced by various types of aerosols with a predominance of mixed type (MT) of aerosols. From the morphological study, it is inferred that the particles are a flake, spherical, irregular, and in flower and aggregated shapes conducted for the TSPM samples collected during SK-323 over the AS. Finally, the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model is used to study the impact of long-distance transported aerosols and identify their sources.

Multicenter, randomized controlled, observer‐blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes—ProNOx1 study

Wound Repair and Regeneration, EarlyView.

Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines†

Technical feasibility, radiation dosimetry and clinical use of 18 F-sodium fluoride (NaF) in evaluation of metastatic bone disease in pediatric population

Abstract

Purpose

The role of ¹⁸F-fluoride (¹⁸F-NaF) PET-CT for the detection of bone metastases in adults is well established and is considered superior to conventional bone scintigraphy. However, data pertaining use of ¹⁸F-NaF PET-CT in pediatric oncology is relatively sparse. The aim of the present study is to retrospectively analyze and share a single-center experience of ¹⁸F-NaF PET-CT in pediatric population and to provide preliminary information regarding imaging technique, feasibility of this modality in young patients and radiation dosimetry measurements in pediatric oncology cases.

Materials and methods

Twenty-four pediatric patients (mean age 8.0 ± 3.9) were included in the study for retrospective analysis. All patients were referred for primary staging or restaging for potential osseous metastatic disease and PET-CT scan was performed by injecting 2.2 MBq/kg (0.06 mCi/kg) of ¹⁸F-NaF.

Results

Nine patients were imaged for primary staging and in all cases increase osteoblastic activity was seen in the primary tumor and of these, metastatic bone disease was identified in 2/9 patients. In the restaging group comprising 15/24 patients, metastatic deposits were identified in 3/15 whilst no disease was seen in the remaining 12 patients. Patients were injected a mean dose of 90.35 ± 22.9 MBq with an estimated mean effective absorbed doses of 2.98 ± 0.75 mSv for ¹⁸F-NaF and 3.37 ± 2.4 mSv for CT alone. Mean cumulative effective dose of ¹⁸F-NaF PET-CT scan was 5.11 ± 2.7 mSv.

Conclusions

¹⁸F-NaF PET-CT may be a feasible alternative to ^99mTc MDP for radionuclide bone scintigraphy in the evaluation of pediatric bone pathology. Due to its better pharmacokinetics, there is potential that osseous staging can be achieved with relatively low doses and with a similar radiation burden as with ^99mTc-MDP imaging.

Examining Risk of Workplace Violence in Canada: A Sex/Gender-Based Analysis

Abstract

Objectives

Workplace violence (WPV) is a serious issue, resulting in significant negative health outcomes. Understanding sex/gender differences in risk of WPV has important implications for primary prevention activities.

Methods

Utilizing two waves of the Canadian General Social Survey on Victimization (N = 27,643), we examined the likelihood of WPV, and sub-categories of WPV, for women relative to men. Using a sex/gender analytical approach, a series of logistic regression models examined how the associations between being a woman and each of the outcomes changed upon adjustment for work and socio-demographic characteristics.

Results

After adjustment for work hours, women were at more than twice the risk of WPV compared to men (odds ratio = 2.12, 95% confidence interval 1.52–2.95). Adjustment for work characteristics attenuated, but did not eliminate this risk. Differences in associations were observed across sub-categories of violence, with adjustment for work characteristics attenuating sex/gender differences in physical WPV, but having minimal impact on sex/gender differences in sexual WPV.

Conclusions

Work characteristics explain a substantial proportion of the sex/gender differences in risk of physical WPV. However, even after adjustment for work characteristics, women still showed an elevated risk relative to men for almost all types of violence (as defined by nature of the violence, sex of the perpetrator, and relationship to the perpetrator) examined in this study. Future investigations should examine why these differences between women and men remain, even within similar occupational contexts.

Femoral artery ultrasound for improving the detection of atherosclerosis in psoriasis

Less painful and effective intralesional injection method for lichen simplex chronicus

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy

Bullous disorders associated with anti-PD-1/PD-L1 therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established.

Early Stage Melanoma and Hematopoietic Stem Cell Transplantation Outcomes

Umweltrecht kompakt

Is Abortion Included in Maternal and Child Health Curricula in the United States?

Abstract

Purpose The purpose of this study is to assess whether Maternal and Child Health (MCH) graduate programs address abortion content in their programs' foundational courses, elective courses, and general curricula. Description Between January and March 2017, we conducted a descriptive study with faculty from the 13 Centers of Excellence in Maternal and Child Health Education, Science and Practice (COEs). We reviewed syllabi and discussed foundational and elective course content via email and key informant interviews with COE faculty. We categorized abortion coverage in foundational courses as "transparent" or "tangential" depending on inclusion of the word "abortion" in course syllabi. We identified electives addressing abortion as "electives including abortion" and courses that focus on abortion as "abortion-specific electives." Assessment Evidence demonstrated that most programs do not transparently address abortion in required course curricula. Only one of 13 COEs transparently addresses abortion in the foundational course(s); seven COEs tangentially include abortion in foundational courses; and all programs address abortion in some capacity though no standard exists to ensure its inclusion. Despite barriers, including avoidance of controversy and fear of losing funding, COEs could address abortion by establishing shared curricular standards, facilitating values clarification and attitude transformation activities, utilizing information-sharing networks, strengthening relationships between MCH programs and abortion-related organizations, and using professional societies. The scope of our study does not allow us to conclude why abortion content is lacking nor the quality of current content. Conclusion MCH programs should transparently incorporate abortion content in foundational and electives courses to educate students on how to engage with complex and sometimes stigmatized public health issues.

The Interprofessional/Family-Centered-Care Observation Rubric (I-FOR): Results of a Multicenter Study of a New Measure of Educational Outcomes

Abstract

Introduction The ability to provide family-centered care (FCC) and the ability to work in interprofessional care teams (IPC) are essential educational outcomes in graduate training programs. Lack of standardized measures leave programs to rely on idiosyncratic methods to monitor outcomes. We developed a faculty observation tool as part of an effort to create a national quality improvement database. We present evidence for the feasibility and validity of the faculty observation tool. Methods Trainees and faculty at four independent training programs participated. Nineteen maternal and child health disciplines were represented. Faculty supervisors rated trainees using the new measure (I-FOR), and trainees completed related subscales of a previously developed self-report measure, the core competency measure (CCM). Faculty provided qualitative feedback regarding the I-FOR in a separate questionnaire. Results Faculty (n = 78) completed the I-FOR on 86 trainees (86/92 = 93%) and reported satisfaction with completing the measures. The I-FOR demonstrated good internal consistency (Cronbach's alpha > 0.930) and test–retest reliability (IPC r = 0.862, FCC r = 0.823, p < 0.001). Greater than 95% of participants reported that the I-FOR accurately addressed the relevant skills for each practice domain. The I-FOR showed no correlation with the CCM. Significant improvements over time in the I-FOR ratings were demonstrated in three out of four programs. Discussion The I-FOR demonstrated good internal consistency and test–retest reliability. Faculty responses provide evidence for the feasibility and validity of the instrument. Self-report and faculty-observation measures both increased with training but were not correlated with each other.

Investigation of Predictors of Newborn Screening Refusal in a Large Birth Cohort in North Dakota, USA

Abstract

Objectives The objective of this study was to identify maternal and provider predictors of newborn screening (NBS) refusal in North Dakota between 2011 and 2014. Methods Records of 40,440 live resident births occurring in North Dakota between 2011 and 2014 were obtained from the North Dakota Department of Health and included in the study. Factor-specific percentages of NBS refusals and 95% confidence intervals were computed for each predictor. Since the outcome is rare, multivariable Firth logistic regression was used to investigate maternal and provider predictors of NBS refusal. Model goodness-of-fit test was evaluated using the Hosmer–Lemeshow test. All analyses were conducted in SAS 9.4. Results Of the 40,440 live births, 135 (0.33%) were NBS refusals. 97% of the refusals were to white women, 94% were homebirths, and 93% utilized state non-credentialed birth attendants. The odds of NBS refusals were significantly higher among non-credentialed birth attendants (p < 0.0001), homebirths (p < 0.0001), and among those that refused Hepatitis B vaccination (HBV) at birth (p = 0.047). On the other hand, odds of NBS refusals were significantly (p < 0.0001) lower among women that had more prenatal visits. Conclusions for Practice This study provides preliminary evidence of association between NBS refusal and provider type, home births, and HBV refusal. Additional studies of obstetric providers, home births and women are needed to improve our understanding of the reasons for NBS refusal to better deliver preventive services to newborns.