Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH), wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA) analog anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH. Effective attenuation of pain is of the utmost importance in patient care. Opioid medications are commonly used in perioperative pain management in addition to providing relief for back -mediated NMDAR potentiation leads via Src-regulated recruitment of PKC and Gα subunits, to an increase in NMDA Ca4 alongside opioids have exhibited recovery of opioid analgesic effect, further substantiating these proposed mechanisms . A study by Gardell et al. performed a microinjection of lidocaine into the RVM or bilateral lesion of the dorsolateral funiculus. The injection abolished tactile and thermal hypersensitivity, indicating the RVM modulates nociceptive input. The same study correlated chronic morphine exposure with upregulation of immune reactivity for calcintonin gene-related peptides and spinal dynorphin  which are upregulated in neuropathic pain states  receptor and decreased norepinephrine release within the brain  VGCCs are of particular interest due to their role in transducing electrical activity into other cellular functions  adamantane-1-carboxylic acid (GZ4), had similar effects on N-type CaRecent studies have shown that the analgesic qualities of gabapentin may not be limited to the interaction at voltage gated calcium channels, but may also include interactions with the interleukin (IL)-10-heme oxygenase-1 (HO-1) signaling pathway. IL-10 is a key immunoregulatory cytokine with anti-inflammatory properties. The cytokine assists in regulating inflammation by suppressing the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules, in addition to regulating antigen-presenting and co-stimulatory molecules in monocytes/macrophages, neutrophils, and T-cells. IL-10 induces heme oxygenase-1 in macrophages through an activated protein kinase cascade .Although the mechanisms of gabapentin as well as opioid–induced hyperalgesia are not completely understood, the efficacy of gabapentin in attenuating OIH has been documented in several case studies. Compton et al. evaluated OIH and the effects of gabapentin in relieving experimental pain in methadone maintained patients. A 2400 mg PO dose was administered daily over a 1-week period, and pain was evaluated using a standardized CP test. The experimental group showed statistically significant improvements in pain threshold and tolerance compared to the control group at peak as well as trough methadone levels. The study concluded that when used in clinically tolerated doses, gabapentin significantly improved CP pain responses in methadone-maintained patients (Compton et al., Another study by Cuignet et al. evaluated gabapentin's ability to reduce OIH in burn patients receiving opioids. Patients were treated with 800 mg of gabapentin three times per day for 21 days. Pain levels were evaluated using a visual analog scale. In the earlier stages of the study, both experimental and control groups had similar pain scores. However, during the rest of the treatment phase, the pain scores became significantly smaller in the gabapentin group as did the required opioid dosage (Hervera et al., Hauer et al. evaluated the effect of gabapentin in two separate cases of infants suffering from neurological impairment resulting from an injury to the central nervous system accompanied and possibly sustained by significant pain. These case reports identified pain sources as nociceptive, peripheral neuropathic, central neuropathic, and visceral hyperalgesic in nature. Significant improvement in apnea following empiric treatment with gabapentin was observed. In both cases, the initial gabapentin dose was 2.5 mg/kg with titration occurring every 4–7 days with the option to titrate more rapidly once dosage tolerance was confirmed (Cuignet et al., OIH will remain an important issue so long as chronic opioid usage remains prevalent in pain control. As such, clinicians should exercise caution in prescribing opioids, and may consider prescribing alternative therapies for pain relief if available. As discussed in prior studies, the use of adjunctive therapies such as gabapentin may be applicable if OIH is suspected. Gabapentin strongly binds to the α-2δ subunit of dorsal horn VGCCs, downregulating their activity and diminishing the propagation of pain signals along afferent neurons. Gabapentin also leads to increased IL-10 and HO-1 pathway activation, promoting anti-inflammatory activity at sites of spinal neuron insult. At this time, the efficacy of gabapentin in mitigating OIH has been demonstrated in animal models and some human case studies. However, few large scale standardized patient studies have been performed to corroborate these findings. We propose the design and implementation of standardized studies investigating gabapentin use in pain patients receiving opioid medications to further elucidate mechanisms underlying OIH as well as to establish a statistical basis for gabapentin use as an adjuvant therapy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Primary cardiac tumours in paediatric population are an unusual occurrence. Although, majority of such tumours are benign (90%), the frequency and type of cardiac tumours in this age group is different from the adult population. There are several consecutive series published in the last decade on cardiac neoplasms. Therefore, this is not only an effort to contribute to the existing literature for better understanding and management of similar patients but also to highlight the importance of early detection either by prenatal imaging or careful evaluation of differential diagnosis of common symptoms. We herein, describe two infants with large cardiac tumours (fibroma and teratoma) both arising from the interventricular septum and underwent surgical excision. A possible role of cardiac remodeling in myocardial tissue healing after extensive tissue resection in such patients is hypothesised through available experimental or limited clinical information. Primary cardiac tumours in paediatric population are an unusual occurrence with reported incidence of 0.17-0.28% as per echocardiographic or autopsy series . Unlike There are several consecutive series published in the last decade on cardiac neoplasms -5. HowevA 12-month-old, Arabic, patient was admitted on emergent basis with multifocal ventricular ectopic beats associated with low cardiac output. He was intubated and resuscitated. Echocardiography demonstrated a large tumour mass filling the apical parts of both the ventricular cavities with severe restriction to the diastolic filling. Other cardiac structures were normal. The CT angiography of the chest revealed a well-defined, near-fluid density, large, space-occupying lesion within the heart involving the anterior-inferior part of the interventricular septum bulging into the ventricular cavity and compromising it Figure . The patA 1–month-old, Arabic, female patient was referred for evaluation of a cardiac murmur due to suspected cardiac tumour. The patient was asymptomatic and clinically the general and physical examination was un-remarkable except that there was a faint precordial systolic murmur. Alfa Feto Protein (AFP) was elevated (118 IU/ml). Echocardiogram revealed a cystic mass (2.5×2.5 cm) attached to the interventricular septum near the tricuspid valve on the right ventricular cavity without any obstruction or compromise to the flow Figure . Other cThe patient underwent surgical excision of the tumour under standard CPB, bicaval and aortic cannulation, aortic cross-clamping and cardioplegic arrest through the right atrial approach at moderate systemic hypothermia. A large tumour mass (4×3 cm) originated from the interventricular septum and filled the ventricular cavity, adjacent to the tricuspid valve Figure . With caFibroma accounts for 12-16% of primary cardiac tumours in children and usually derived from connective tissue fibroblasts -6. CardiCardiac teraromas are the second most common tumour in the neonates -5. The uIn infants and children, tumour presentation is often variable due to its location and size. Cardiac tumours are frequently hemodynamically relevant due to obstructive features at various locations within the heart. It includes obstruction to the ventricular inflow and outflow tracts, coronary arteries or the valves. Even ventricular arrhythmias may be the presenting features. Furthermore, tumour size matters in two different ways. Either tumour mass obstructs flow within cardiac chambers that may be well-tolerated for a long period or tumour encroaches on the wall of surrounding structures and presents with arrthythmia or cardiogenic shock (patient 1). Our second patient had a relatively-late presentation because some time must have been taken to grow an intramural lesion to attain 4 cm in diameter.Echocardiography is the mainstay of non-invasive diagnostic tool that depicts tumour size, location, surrounding structures and any functional impairment. Cardiac catheterization is usually not necessary except when there are large tumour compromising coronary arteries or associated pathologies.Supplemental diagnostic imaging may include CT or MRI scanning because it provides sectional views of cardiac and mediastinal structures from various angles. In addition, it delineates tissue composition to identify solid, liquid, fatty, haemorrhagic, calcific or cystic nature of the tissue . CurrentIt is always doubtful to ascertain which patients need surgery and which will benefit from conservative follow-up . SurgicaIn symptomatic patients, if the resection of the cardiac tumour is not achievable, or a large resultant structural cardiac defect is anticipated, cardiac transplantation remains a possibility where there is no evidence of metastatic involvement. However, long-term results are questionable .When tumour is encapsulated it keeps the integrity of the myocardial tissue without destroying or infiltrating them. Thus, after tumour removal relatively intact muscular layers can restore geometry and function favourably. This is similar mechanism we observe after intraluminal mass removal, i.e. cavity dilation goes back to normal. However, majority of the large cardiac tumours in paediatric age group are associated with structural change in the myocardial tissue either due to destruction or infiltration effect. In addition, surgical resection causes further damage or tissue loss. This fact prompts us to think about the mechanism of repair and favourable outcome in paediatric population with cardiac tumours. In our opinion, cardiac remodeling plays an important role in restoration of size, shape and function of the myocardial tissue and the heart in such patients. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reverse remodeling has recently been a goal of heart failure therapy world-wide . In expeCardiac tumours in paediatric population must be considered in the differential diagnosis of cardiac insufficiency, valvular disease, arrhythmias, cardiomegaly or presence of murmurs. The prenatal screening should use appropriate imaging tools for early detection of such tumours. Surgical consideration should include invidualised, early and safe management approach for symptomatic patients aiming not only to resect the entire tumour mass with sufficient margin but more importantly restore best possible haemodynamics with a careful follow up. The role of cardiac remodeling and pharmacological intervention to alter this process may have future implications especially to heal damaged myocardial tissues secondary to large size of tumours or surgery.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Most patients with facial scarring would value even a slight improvement in scar quality. Botulinum toxin A is widely used to alleviate facial dynamic rhytides but is also believed to improve scar quality by reducing wound tension during healing. The main objective was to assess the effect of Botulinum toxin on scars resultant from standardized upper lip wounds.In this double-blinded, randomized, vehicle-controlled, prospective clinical trial, 60 consecutive consenting adults undergoing cleft lip scar revision (CLSR) surgery between July 2010 and March 2012 were randomized to receive botulinum toxin A (n = 30) or vehicle  injections into the subjacent orbicularis oris muscle immediately after wound closure. Scars were independently assessed at 6-months follow-up in blinded fashion using: Vancouver Scar Scale (VSS), Visual Analogue Scale (VAS) and photographic plus ultrasound measurements of scar widths.58 patients completed the trial. All scar assessment modalities revealed statistically significantly better scars in the experimental than the vehicle-control group.Quality of surgical upper lip scars, which are oriented perpendicular to the direction of pull of the underlying orbicularis oris muscle, is significantly improved by its temporary paralysis during wound healing.NCT01429402ClinicalTrials.gov  A cutaneous scar is the end result of a complex wound healing process that follows dermal injury The muscles of facial expression lie superficially, do not have bony attachments and create expressions by altering the tension of adjacent skin. However, skin tension that is perpendicular to an incision or laceration is known to increase the risk of unfavorable scarring as a result of the distracting forces exerted on the healing wound A standardized method of cleft lip scar revision (CLSR) has been established for more than a decade at our center. The design of incisions, sutures used and postoperative care are all protocolized. CLSR incisions are unavoidably perpendicular to the direction of pull of the underlying orbicularis oris muscle, which therefore exerts unfavorable forces across the sutured wound . We routWe hypothesized that temporary paralysis of the orbicularis oris muscle with botulinum toxin may improve the CLSR scar and tested this with a randomized, double-blinded, prospective, vehicle-controlled clinical trial. This is the first such trial that has evaluated the effects of botulinum toxin on scars from uniformly sustained, orientated, repaired and managed upper lip wounds in a single ethnic population.This was a randomized, double-blinded, prospective, vehicle-controlled, two-armed parallel clinical trial designed to investigate whether the injection of botulinum toxin into a perpendicularly oriented muscle (orbicularis oris) subjacent to a constant facial (CLSR) wound immediately after completion of surgery affected the quality of the resultant scar .The trial was approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital. After clear explanation of the study, an IRB approved written informed consent was provided by all participants. If patient was minor, the IRB approved written informed consent was provided by parents or guardians. The date at which the ethics committee approved the study was 16 October 2009, the date that patient recruitment started was 9 July 2010 and the date that follow-up completed for the final patient was 20 March 2012.This study was registered at clinicaltrials.gov [ID NCT01429402]. Registration occurred after the trial began due to administrative difficulties with the registration process. The authors confirm that all ongoing and related trials for this drug are registered.The sample size was calculated based on the results of a pilot study. Ten consecutive outpatients underwent upper lip scar evaluation in March 2009 using the Vancouver Scar Scale (VSS) and presented a mean score of 4.6±1.26 . If treatment could improve VSS score by 1, which was considered clinically significant, approximately 26 patients per group would have been necessary to provide a result with a real significance (using the same SD and considering the standard α error of 0.05 and a power of 0.8). Assuming a 10% non-compliance rate for follow-up evaluation, the sample size was increased to 30 per group.Between July 2010 and March 2012, sixty consecutive patients were enrolled for randomization having satisfied the following criteria. Inclusion criteria were: (1) adult (16 years or older) Oriental Taiwanese patients who desired elective CLSR surgery; (2) moderate-to-severe secondary scar deformity following primary cleft lip repair that warranted revision surgery; (3) valid written informed consent provided for surgery and trial inclusion. All CLSRs were performed at the Craniofacial Center of Chang Gung Memorial Hospital, Taiwan.A specialized nurse, who was independent of the study, prepared the encoded vials. Experimental group vials contained 0.6 ml of normal saline with 15 units of botulinum toxin A . Vehicle-control group vials contained 0.6 ml of normal saline. All vials appeared identical except for their randomization code and patient identification.Patients were block randomized to a 1∶1 ratio by an independent third-party specialized trials nurse into the experimental or vehicle-control group. Randomization codes were not revealed to anyone until after completion of the entire study. Patients, investigators, study personnel and outcomes assessors therefore remained blinded throughout the investigation S1 Check.The lip scar was revised using a modified rotation advancement cheiloplasty as previously described Nylon sutures were removed six days postoperatively. To reduce wound tension caused by the adjacent risorius, zygomaticus major and zygomaticus minor muscles, both cheeks and the upper lip suture line were taped as per our routine for 6 months. Additionally, silicone sheeting was applied overnight as per our routine for 6 months. Compliance with both practices was consistent for all patients. All complications, such as hematoma, infection, wound dehiscence, oral incompetence, eating/drinking dysfunction and drug allergy, were logged if encountered.Primary and secondary end points were Vancouver scar scale (VSS) score , Visual analogue scale (VAS) and scar width, respectively. At six months follow-up, two plastic surgeons (PKTC and CSC) examined the patients in the outpatient clinic of Chang Gung Memorial Hospital. They were blinded to which group patients belonged. Scars were assessed using the VSS and assigned the mean score of the two observers.For photographs, one standard surgical ruler was placed over the lower lip and a frontally orientated photograph of the patient was taken at 6-months follow up. The same professional craniofacial medical photographer took all photographs. Patient's photographs were subjectively assessed using VAS by five independent examiners (two Attending Plastic Surgeons and three laypersons). All examiners were both independent of the patients' care and blinded to their treatments. They were asked to score the scars on the photographs using a standard Visual Analogue Scale (VAS) graded from 0 (worst possible scar) to 10 (best possible scar).Objective scar width measurements were performed using photography and ultrasonography. The scar was measured at two points with Photoshop  using the ruler as a control reference. The First Point was 1 mm above the white roll and the Second Point was 1 mm below the turning incision line, which is located close to the nasal sill . The scaA commercial 12-MHz ultrasound transducer and imager  was also used to quantify scar width. The transducer was placed with its upper border touching the columella-philtral junction, upper lip imaging was obtained and the scar width measured at the skin surface . The ultInter-observer reliability of the VSS and VAS were tested using Cronbach α. Inter-observer reliability of photographic measurements was assessed with Pearson correlation by comparing two sets of measurements performed by two independent raters. Intra-observer reliability of ultrasound measurements was assessed with Pearson correlation by comparing two sets of measurements performed by the same rater.All statistical analyses were conducted using SPSS software . Differences between VSS scores, VAS and between scar widths obtained photographically and ultrasonographically were compared. The independent t-test was used to compare groups. Statistical significance was defined if p was less than 0.05. Data are presented as mean ± standard deviation unless otherwise stated.Thirty patients in the experimental group received botulinum toxin injections and thirty patients in the vehicle-control group received normal saline injections, as described, immediately after completion of CLSR. Fifty-eight patients completed six months of follow-up; two patients in the vehicle-control group failed to return for postoperative assessments. No complications were encountered .The mean ages for the experimental group and vehicle-control group were 24.70±7.16 versus 21.87±8.00. There were 12 males and 18 females with 20 left and 10 right cleft lips in the experimental group. There were 14 males and 14 females with 20 left and 8 right cleft lips in the vehicle control group.The VSS score for the experimental group was significantly lower than that of the vehicle-control group . Inter-observer consistency in using the VSS score was high (Cronbach α = 0.936).The VAS score in the experimental group was significantly better than in the vehicle-control group . Inter-observer consistency was high (Cronbach α = 0.923)According to photographic measurements, the scar was significantly narrower at both the First Point  and the Second Point  in the experimental than in the vehicle-control group. Inter-observer consistency was high for the photographic data . This was also the case according to ultrasonographic measurements . Intra-observer consistency was high for the ultrasonographic data .Facial scars can be cosmetically disfiguring and may, in some patients, cause functional impairment and psychosocial withdrawal Synergistic contractions of the facial muscles are responsible for facial expressions. Since these muscles do not have bony insertions and lie very superficially, their actions exert tension across adjacent skin and subcutaneous tissue. If a wound is orientated perpendicular to the direction of the underlying facial muscle fibers, the muscular tension exerts a distracting effect on the healing wound edges and increases the risk of an undesirable hypertrophic or widened scar . ConsequA secondary cleft lip deformity is one that arises despite primary surgical treatment of the cleft lip. The principles of CLSR are cleft scar excision, anatomical repair of the orbicularis oris muscle, and correction of asymmetries noted in the Cupid bow and philtral columns. Unfortunately, CLSR wounds are unavoidably orientated perpendicular to the line of pull of the subjacent orbicularis oris muscle, which is in constant use during daily life for speech, eating, drinking, blowing, sucking, and a variety of facial expressions. These repetitive bouts of distracting tensional forces inflict micro-trauma to the healing wound, leading to prolongation of the inflammatory response and ultimately increased fibrosis Firstly, taping of the skin is commonly used for its splinting effect, which is known to improve scarring by protecting healing cutaneous wounds from tensional forces Botulinum toxin causes chemical muscular paralysis The same effect may also be exploited to reduce tension around healing facial wounds. Gassner et al demonstrated that botulinum toxin injections improved scarring from facial wounds in non-human primates The present trial was therefore carefully limited to CLSR as a consistent model of lower facial wounding with a known risk of hypertrophic scarring and consistent perpendicular orientation to underlying expressive musculature. These patients and wounds were standardized in terms of ethnicity, mechanism of sharp incisional injury, CLSR design and resultant wound orientation, repair method, sutures and suturing techniques used, suture removal time, postoperative taping and silicone application, and lack of postoperative complications that affect scarring, such as dehiscence, infection and hematoma. The critical difference was the content of the randomized post-repair injections. Postoperative subjective assessments were semi-quantitatively performed using the validated VSS and VAS, and objective quantitative measurements were performed using two modalities that each presented high inter- and intra-observer consistency. Accordingly, we were able to draw a robust conclusion that the botulinum toxin injections resulted in significantly improved CLSR scars , due to Limitations of this study include, firstly, that interpretation of the absolute boundaries of a cutaneous scar is not binary and therefore may be subject to variation when performing scar width measurements. Intra-observer reliability analyses, however, were high. Secondly, since the width of a scar may not be uniform throughout its length, the points at which scars widths were measured, photographically or ultrasonographically, may not have been representative of the entire scar.This randomized, double-blinded, vehicle-controlled, prospective clinical trial demonstrated that botulinum toxin significantly improved quality of scarring following CLSR.S1 ChecklistCONSORT checklist.(DOC)Click here for additional data file.S1 ProtocolOriginal protocol of study.(DOCX)Click here for additional data file.S1 DataRaw data of study.(XLSX)Click here for additional data file.


Even after quitting illicit drugs, tobacco abuse remains a major cause of morbidity and mortality in former injection drug users. An important unmet need in this population is to have effective interventions that can be used in the context of community based care. Contingency management, where a patient receives a monetary incentive for healthy behavior choices, and incorporation of individual counseling regarding spirometric “lung age”  have been shown to improve cessation rates in some populations. The efficacy of these interventions on improving smoking cessation rates has not been studied among current and former injection drug users.In a randomized, factorial design study, we recruited 100 active smokers from an ongoing cohort study of current and former injection drug users to assess the impact of contingency management and spirometric lung age on smoking cessation. The primary outcome was 6-month biologically-confirmed smoking cessation comparing contingency management, spirometric lung age or both to usual care. Secondary outcomes included differences in self-reported and biologically-confirmed cessation at interim visits, number of visits attended and quit attempts, smoking rates at interim visits, and changes in Fagerstrom score and self-efficacy.Six-month biologically-confirmed smoking cessations rates were 4% usual care, 0% lung age, 14% contingency management and 0% for combined lung age and contingency management (p = 0.13). There were no differences in secondary endpoints comparing the four interventions or when pooling the lung age groups. Comparing contingency management to non-contingency management, 6-month cessation rates were not different , but total number of visits with exhaled carbon monoxide-confirmed abstinence were higher for contingency management than non-contingency management participants , and more contingency management participants showed reduction in their Fagerstrom score from baseline to follow-up .While lung age appeared ineffective, contingency management was associated with more short-term abstinence and lowered nicotine addiction. Contingency management may be a useful tool in development of effective tobacco cessation strategies among current and former injection drug users.NCT01334736 .Clinicaltrials.gov Injection drug users (IDUs) have among the highest prevalence of tobacco dependence, yet represent an understudied population in terms of smoking cessation strategies–4. IDUs Studies have consistently demonstrated that the majority of illicit drug users are interested in quitting smoking, 11. As The AIDS Linked to the Intravenous Experience (ALIVE) study, a prospective, longitudinal cohort of persons with a history of injecting drugs followed in Baltimore, Maryland since 1988, represents an ideal population to explore novel smoking cessation interventions. This coAs described previously, 30, ALIPrior to study initiation, 120 sequentially numbered opaque sealed envelopes were externally prepared that included random assignment to one of four interventions. Randomization sequence was computer-generated using a block randomization approach with randomly ordered four and eight sample blocks. After informed consent was obtained and baseline data including smoking-related questionnaires, assessment of self-efficacy and intention to quit smoking, exhaled carbon monoxide (eCO) level and spirometry were completed, study staff was provided the next sequential envelope which assigned the intervention.The overall design of the study included one baseline visit and six follow-up visits over six months. All visits occurred at the ALIVE research clinic site. Assessment of eligibility, informed consent, randomization and spirometry measurement occurred at the baseline visit. Follow-up visits occurred at one, two and four weeks, then two, three and six months from baseline visit. An increased frequency of visits early in the study was included to enhance protocol compliance.At baseline and follow-up visits, all participants completed smoking-related questionnaires, assessment of self-efficacy and intention to quit smoking and eCO measurement. At all visits, participants also received a brief standardized counseling session on the harms of smoking and were offered information on smoking cessation resources available in the community. If the participant inquired about nicotine replacement therapy, he or she was advised to contact their primary care provider to discuss potential therapeutic options. Blood was obtained for serum cotinine analysis at six month visits.At baseline and follow-up visits, the usual care group reviewed baseline spirometry results of their lung function reported as a percentage of predicted values, communicated in a standardized written format. Lung function was first described as the numerical percent predicted value, and defined as normal if the forced expiratory volume in one second (FEV1) was equal or greater to 80% of predicted value. If normal, the report stated “Even though your lung function is normal, it is still important to quit smoking to prevent future damage to the lungs.” If the results were abnormal, the report stated “This suggests that your lungs may already be damaged by smoking. Quitting smoking now can slow the rate of damage of the lungs.”Individuals randomized to contingency management received similar interventions as the usual care group. Additionally, it was explained to participants that they would receive monetary compensation for biological confirmation of tobacco cessation. At each visit, exhaled carbon monoxide levels were checked, and if eCO was <7 ppm, participants received compensation in a manner modified from the methodology of Shoptaw. The firFor individuals randomized to lung age intervention, spirometric results were reviewed in the context of lung age. Visual Individuals randomized to this intervention received a combination of the lung age and contingency management protocols described above.Pre-bronchodilator spirometry FEV1 and forced vital capacity (FVC) was measured using KOKO® pneumotachometers  in accordance with American Thoracic Society guidelines. PercentThe primary outcome of this study was the difference between interventions in six-month biologically-confirmed smoking cessation, defined as self-report of non-smoking in the last seven days combined with negative eCO and serum cotinine at final study visit. Secondary outcomes included differences by intervention in number of visits attended, smoking rates at interim visits (self-report and eCO), number of quit attempts, change in Fagerstrom score, and alterations in self-efficacy. All analyses were based on intention-to-treat. Comparison of outcomes across intervention was performed using chi2 test with Fisher’s exact p-value for small samples of categorical outcomes and t-test or kruskal-wallis for continuous values as appropriate. A p-value of <0.05 was used to define statistical significance. It was determined a priori that if no interaction between lung age and contingency management was observed, individual interventions would be pooled for analysis .A total of 265 ALIVE participants were screened to identify 100 eligible and interested participants for this study . Using less stringent criteria for smoking cessation  also did not yield differential six month cessation rates across all four interventions. There were no substantial differences in the secondary endpoints of change in smoking rates (self-report and eCO) at interim visits, change in Fagerstrom score, total number of visits attended, alterations in self-efficacy and number of quit attempts comparing the four interventions.Because there was neither an effect of lung age on outcomes nor an interaction between contingency management and lung age, we compared outcomes of the contingency management interventions to non-contingency management interventions  Table  and3. CIn this study, we examined the impact of contingency management and the use of spirometric lung age as motivational tools to improve smoking cessation rates among IDUs. While neither intervention, when compared to usual care, was associated with a statistical change in six-month biologically-confirmed cessation rates, we did observe that contingency management interventions were associated with more short-term abstinence as measured by exhaled CO and with lower nicotine addiction as assessed by Fagerstrom score. We did not observe any effect of using spirometric lung age as tool to change smoking behavior or nicotine addiction in this population, and in fact observed that spirometric lung age may have attenuated the effect of contingency management when these interventions were combined.Contingency management has been reported to enhance smoking cessation rates in opiod-maintained patients–22. MostContingency management for drug abuse treatment has been extensively evaluated, with consistent data from high-quality studies demonstrating benefit for abuse of varied substances  in different settings –44. SimiWhile contingency management did impact some outcomes of this study, we did not observe any differential changes in smoking behaviors or perceptions associated with the use of spirometric lung age as a motivational tool. This differs from several prior reports in varied study populations. Parkes and colleagues conducted a randomized controlled trial of smoking cessation incorporating lung age-based counseling in 561 smokers from United Kingdom outpatient practices. At 12 mSeveral theoretical models of health behavior change, including the health belief model, protection motivation theory and precaution adoption models, propose that perceptions of personal vulnerability to the harms of smoking are key to motivating smoking cessation–60. AddiUnique strengths of this study include the focus on an under-studied population with high tobacco dependence, a study design permitting evaluation of the independent and synergistic effects of two interventions, and the near-complete 6-month follow-up. This study has some limitations. The small sample size of this study limits the ability to determine the efficacy or estimate the magnitude of the effect of contingency management or spirometric lung age on smoking cessation. The data from this study can be used to inform larger trials testing these interventions. The durability of benefits from contingency management after completion of the intervention is not known, but will be evaluated with on-going follow-up. While the overall rates of cessation were low, a six month 7-11% biological cessation rate is likely substantial in this challenging population of IDUs. Intentionally, this study lacks generalizability outside of urban, minority populations dealing with substance abuse. Our goal was to examine specific cessation interventions among drug users, as this population has high smoking prevalence, substantial tobacco-related disease burden, extremely low cessation rates, and has been greatly understudied in terms of cessation interventions. This study demonstrates that tobacco cessation interventions can be effectively implemented in this population. Novel cessation strategies, such as incorporating mobile health  tools to improve smoking cessation among marginalized, underserved populations holds promise for improving access and efficiency to smoking cessation interventions and towards reducing the tobacco-related disparities that currently exist.In summary, we have demonstrated that contingency management, but not spirometric lung age message, as a motivational tool for smoking cessation leads to more short-term abstinence and lower nicotine addiction over a 6-month period. While definitive benefit on biologically-confirmed smoking cessation at 6 months was not achieved in this study, our findings demonstrate that contingency management interventions are feasible among urban drug-using populations and leads to favorable modifications in smoking behavior, specifically cessation attempts and in reduced levels of nicotine addiction. Larger trials among drug-using populations are appropriate to definitively establish if contingency management is of benefit in this population. Ultimately, contingency management may help decrease the substantial burden of tobacco dependence in similar underserved populations with excessive tobacco use.


Chaos carolinense). In this ancient organism, the cells are able to survive in extreme environments such as lack of food, thermal and osmolarity fluctuations and high levels of reactive oxygen species. Their mitochondrial inner membranes undergo rapid changes in three-dimensional organization upon food depletion, providing a valuable model to study this subcellular adaptation. Our data show that cubic membrane is enriched with unique ether phospholipids, plasmalogens carrying very long-chain polyunsaturated fatty acids. Here, we propose that these phospholipids may not only facilitate cubic membrane formation but may also provide a protective shelter to RNA. The potential interaction of cubic membrane with RNA may reduce the amount of RNA oxidation and promote more efficient protein translation. Thus, recognizing the role of cubic membranes in RNA antioxidant systems might help us to understand the adaptive mechanisms that have evolved over time in eukaryotes.Possibly the best-characterized cubic membrane transition has been observed in the mitochondrial inner membranes of free-living giant amoeba ( Biomembranes are traditionally viewed as flat sheets of phospholipid bilayers dividing the cytoplasm into multiple subcellular compartments with specialized functions. However, biomembranes may also fold up into three-dimensional periodic arrangements termed ‘cubic membranes’  1,2]. C,2. C1,2]Escherichia coli, levels of fumarase C, which is insensitive to superoxide anions, increase during oxidative stress, probably to replace fumarases A and B which are susceptible to damage by superoxide anions [However, living organisms developed several other defence mechanisms to cope with oxidative stress. For example, in the unicellular organism e anions . In othee anions . These oChaos carolinense) contain greater levels of free radicals than fed amoebae [Chaos mitochondria [Chaos exhibit a high content of very long-chain polyunsaturated fatty acids (VLC-PUFAs), specifically the C22 : 5n-6 modified phosphatidylcholine plasmalogen, phosphatidylethanolamine plasmalogen and phosphatidylinositol species, that appear to be critical for development and maintaining highly ordered yet curved interwoven cubic membrane structures [It had been established that starved amoebae . We also study the ability to provide ODN uptake via cubic membranes [in vitro (We note that the mitochondria with cubic membrane organization isolated from starved amoeba embranes . Specifiembranes . Moreovein vitro . Hence, It is believed that the alterations of gene expression and faithful translation of RNAs are the key factors of the metabolic changes essential for cell survival and the rapid organismal adaptation to new environmental stimuli. Oxidative damage to both coding and non-coding RNAs may therefore affect the regulation of gene expression and, potentially, result in the failure of protein synthesis. This failure may impair the organismal capacity of flexibly adapting to a novel or unusual internal or external environmental stimulus . Furthersn-1 position and enriched in PUFAs at sn-2 position of the glycerol backbone [Plasmalogens are a unique class of ether phospholipids with a vinyl ether bond at backbone . They fobackbone . We are backbone ,24,25.et al. [A number of studies have shown that plasmalogens are protective in lipid peroxidation ,27. Sindet al. .The free radical species formed during the peroxidation of the vinyl ether bond may either be more stable or be less efficient to abstract hydrogen than the alkyl radicals produced during the peroxidation of PUFAs . Also, iIn addition to the mitochondrial antioxidant enzymes, plasmalogens can limit the diffusion of ROS within the different compartments of cubic membrane because of their proneness to be peroxidized. This mechanism would limit the intercellular transmission of ROS and that the oxidative cascade might spread to RNAs segregated into the inner compartments of cubic membranes. Some support for this proposition comes from experimental observations where cubic membranes strikingly correlate with viral infections; notably, RNA viruses . Viral ePlasmalogen oxidation and VLC-PUFA peroxidation in phospholipids of cubic membranes have a number of negative downstream effects on the physical properties and structure of the membranes, such as the decrease in their fluidity and increases in lamellar membrane formation rather than cubic organization. However, an increasing body of evidence suggests that peroxidized phospholipids can be repaired by the enzymes phospholipase A2 and acyl-transferase . While uIn view of these observations, we propose here an integrative model  where na


PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test , controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters  While considerable research has examined the neural correlates of anxiety in adolescents, few studies have examined these correlates in children with symptoms of ASD. Here we investigate whether aberrations in reward processing underlie the co-occurrence of ASD traits and anxiety and whether they predict the new onset of anxiety in youth with ASD traits.Anxiety is common in youth with autism spectrum disorder (ASD)12 with aberrant processing of primary,13 social15 and monetary rewards16 reported in children and young people with ASD. Furthermore, studies in youth with ASD have reported associations between brain activations during reward processing and ASD traits such as social communication difficulties17 and restricted and repetitive behaviors.18 Some19 but not all studies16 have suggested that the extent to which reward processing in youth with ASD differs from typically developing controls may depend on reward type.Reward processing has been proposed to be central to ASD,21 Anxiety disorders and behavioral difficulties are consistently identified as the most common comorbidities in youth with ASD.22 These comorbid disorders are associated with aberrant reward processing in their own right, and therefore could influence reward processing in youth with ASD. Young people with anxiety show disrupted frontostriatal activation when anticipating reward25 and when receiving reward feedback.26 Youth with behavioral difficulties, in particular oppositional defiant disorder (ODD) symptoms and irritability, often show aberrant responses when rewards fail to appear, perhaps due to the frustrative nature of negative outcomes.28Surprisingly, however, the question whether these reward aberrations are inherent to ASD symptoms or related to disorders that co-occur with ASD remains unanswered. This is a key question considering that less than 10% of children with ASD are free of any concomitant disorders according to some studies.30 In the other model, the neural correlates of the comorbidity are unique, that is, not seen with any of the two disorders. This distinction is crucial from an etiological and clinical perspective, as finding unique correlates would suggest that the comorbidity might represent a separate nosological process, what has been termed a ‘third independent disorder'.31 In addition, our aim is to establish the potential predictive value of neural correlates of comorbidity. Using a longitudinal design, we examine whether neural correlates found in people with concurrent ASD traits−anxiety comorbidity can be used to predict the likelihood of new-onset anxiety in those with high ASD traits only. We achieve this aim in two steps.The aim of the present study is to use functional magnetic resonance imaging (fMRI) to disentangle the interplay of ASD traits and anxiety during reward processing. To enable the investigation of these factors, we use a large, community-based sample of adolescents with high vs low levels of ASD traits and anxiety symptoms, who completed a widely used, modified monetary incentive delay (MID) fMRI reward task. Our aim is to distinguish between two important models of comorbidity. One model assumes that neural correlates of comorbidity simply reflect the co-occurrence of neural mechanisms seen with each ASD traits and anxiety separately.30First, we test the independent influence of each ASD traits and anxiety on brain correlates of reward processing, and also examine possible interaction effects between ASD traits and anxiety. The latter is particularly important in order to assess whether combined ASD traits and anxiety is associated with distinct etiological mechanisms.successive comorbidity32 between ASD traits and anxiety, that is, whether such brain activations predict the new onset of anxiety in those with high ASD traits. To achieve this, we run regression models with anxiety at 2-year follow-up as the outcome, and brain activations (relevant to the comorbid group) as the predictor of interest, separately for participants with low vs high ASD traits, controlling for baseline anxiety. To capture major elements of reward processing, we enquire about two key stages: reward anticipation and reward feedback. The former is often associated with heightened frontostriatal activation in youth with anxiety symptoms,33 whereas negative feedback is likely to elicit frustration, possibly related to irritability/ODD symptoms that are common in ASD5 but also in anxiety.34 For completeness, we also examine positive reward feedback, since youth with ASD tend to show reduced responsiveness to rewards in fMRI studies.36 By using a community sample we avoid the risk of referral bias typical of clinical or convenience samples, a pertinent issue when investigating comorbidity,29 although the extent to which our results translate to youth who meet the diagnostic criteria for ASD remains to be tested. We also follow the emerging evidence that ASD traits, but also the mechanisms underlying them, fall on a continuum within the general population.38Second, we assess whether the brain activations found in our cross-sectional interaction analyses represent a biomarker that also predicts 39 All local ethics research committees approved the study. Written informed consent was obtained from a parent or guardian, and verbal assent was obtained from the adolescent. Any adolescents with IQ<70 were excluded from this study. After quality control for neuroimaging and behavioral tests, final sample sizes were 1472 for reward anticipation, 1601 for negative feedback and 1726 for positive feedback. Differences in sample sizes across conditions are due to some fMRI contrasts being non-estimable for some participants at the first-level analysis stage. Calculation of the optimum number of participants needed for an fMRI study is difficult to perform a priori. Conventional calculations to compute statistical power for a given effect size are not applicable in imaging, primarily because the MR signal in each voxel has a large degree of spatial and temporal variability. Previous studies assessing the reliability of fMRI group-level analyses have suggested that a sample size of n=20−24 is sufficient to obtain good statistical power and accurate activation maps.42Data were obtained from the Imagen database established across eight sites in France, UK, Ireland and Germany, which includes 2223 adolescents recruited in schools. We used data from the first (age around 14 years) and second waves (age around 16 years) of Imagen. Recruitment and assessment procedures were described in detail previously.IQ was estimated with the Wechsler Intelligence Scale for Children—Fourth Edition, WISC-IV,43 in wave 1 and entered into Psytools , an online computer platform. Two standardized indices were calculated from the WISC subtests applied during neuropsychological testing for Imagen: Verbal Comprehension (derived from Vocabulary and Similarities subtests) and Perceptual Reasoning (derived from Block Design and Matrix Reasoning subtests).ASD traits were assessed in wave 1 using the ASD section from the Development and Well-Being Assessment , a parent-reported, self-administered structured diagnostic interview with 15 questions about social difficulties, 14 questions about restricted, repetitive behaviors and interests, and three questions about language development to assess DSM-IV-defined ASD symptoms. The diagnostic algorithm derived from the DAWBA ASD module shows strong agreement with that from the Autism Diagnostic Interview—Revised46 and has a high predictive value for ASD diagnoses in community settings.47 In line with the newest characterization of ASD,48 we classified participants as having ‘high' levels of ASD traits if their parents/carers reported three or more symptoms on the social difficulties subscale and three or more symptoms on the restricted and repetitive behaviors subscale of the DAWBA ASD section. Based on this criterion close to 5% of the sample had high ASD traits .52 The scale includes three questions about anxiety, one question about somatic symptoms and one about low mood. A score of 5 and above indicates substantial risk of clinically significant emotional problems52 and was used as a cut-off. We used emotional symptoms instead of ‘any anxiety' in confirmatory analyses (see below) to ensure that our findings were not measure-specific.Additional relevant symptoms of hyperactivity, conduct problems and functional impairment were assessed using the parent-reported SDQ.5254 to study neural responses to reward. The task has three conditions: reward anticipation (anticipation of large win versus anticipation of no win), receipt of negative feedback (feedback of missed large win versus feedback of missed no win) and positive feedback (feedback of hit large win versus feedback of hit no win). A detailed description of the task is provided in In wave 1, the participants performed a modified version of the well-established MID taskStructural and functional magnetic resonance imaging (MRI) data were acquired at eight Imagen assessment sites with 3-T MRI scanners of different manufacturers . The scanning variables were chosen to be compatible with all scanners. The same scanning protocol was used at all sites. In brief, high-resolution T1-weighted three-dimensional structural images were acquired for anatomical localization and co-registration with the functional time series. fMRI blood-oxygen-level dependent (BOLD) images were acquired with a gradient-echo, echo-planar imaging sequence. For the MID task, 300 volumes were acquired for each subject. Each volume consisted of 40 slices aligned to the anterior commissure−posterior commissure line  acquired in a descending order. The echo time was optimized  to provide reliable imaging of subcortical areas. See t-test (two-tailed), separately for participants with low and high ASD traits.We first tested whether participants were motivated by the potential of winning a reward. As a proxy of task engagement, we compared mean response accuracy in ‘no win' and ‘big win' trials using a paired-samples www.fil.ion.ucl.ac.uk/spm). Analyses were performed at an a priori voxel threshold of P<0.01 and cluster threshold of P<0.05 with family-wise error (FWE) correction. Gender, handedness, site of scanning, WISC Verbal Comprehension and WISC Reasoning were included as covariates in all analyses, in line with previous studies.56 All findings are reported at whole-brain level. , which confirmed statistically equal variances between the groups.)Imaging analyses were performed using the Statistical Parametric Mapping suite  vs high (band 2 or above)) to test for main effects of ASD traits and anxiety, and an ASD-by-anxiety interaction, separately for reward anticipation, negative and positive feedback conditions. Where an ASD-by-anxiety interaction was found, we ran follow-up We repeated the above ANOVAs twice, first adding ODD and then depression into the model as potential confounders.t-tests using the SDQ emotional symptoms subscale (cut-off at 5) instead of DAWBA-defined ‘any anxiety'.To ensure that our main findings were not measure-specific, we ran confirmatory ANOVAs and 57 and the ROIs were extracted from the contrast maps for a given reward condition, using MarsBaR toolbox in SPM based on the WFUPickAtlas toolbox definitions.58 To ensure that the ROIs predicted new onset of anxiety, baseline anxiety status was added to the model as an additional predictor. We also added baseline ASD traits (continuous variable) to the model, to ensure that the predictions were not driven by the severity of ASD-specific impairments. To assess the specificity of brain predictions, regressions were run separately within low and high ASD trait groups. If an ROI predicted new-onset anxiety in one group but not the other, a regression model was run across the whole sample with an interaction term between ROI activations and ASD traits (low vs high) to identify the strength of a possible interaction. These analyses were not corrected for multiple comparisons since the ROIs were pre-defined based on our cross-sectional results.Our second aim was to assess whether the brain activations found in cross-sectional interaction analyses above are (a) a phenotypic manifestation of the co-occurrence between ASD traits and anxiety, or (b) whether they represent a biomarker that predicts not only cross-sectional, but also successive comorbidity between ASD traits and anxiety. To test this we conducted logistic regression analyses with anxiety (low vs high) at 2-year follow-up as the outcome, and brain activations found in our cross-sectional interaction effects as predictors of interest. Analyses were run in Stata 11,As expected, participants with high ASD traits scored significantly higher on all subscales of the DAWBA ASD section compared to those with low ASD traits  and had t-tests revealed that participants with high and low ASD traits both responded more accurately in ‘big win' compared to ‘no win' trials =3.90, P<0.001; low ASD traits: 67.4% vs 53.8%, t(1401)=28.49, P<0.001), suggesting that both groups were motivated by the potential of winning a reward. The increase in response accuracy between ‘no win' and ‘big win' trials was higher for those with low vs high ASD traits, t(1470)=2.97, P=0.003, d=0.39.Paired-samples We first conducted an ANOVA to test the effects of ASD traits and anxiety on brain activations during reward anticipation.n=70) showed lower BOLD responses in the right superior frontal gyrus (SFG) extending to the anterior and midcingulate regions relative to youth with low ASD traits (n=1402). Participants with anxiety symptoms displayed increased activation in the right middle frontal and middle temporal gyri (MFG and MTG), irrespective of ASD-trait severity.We found a main effect of ASD-trait severity and a main effect of anxiety . ParticiANX relative to all other groups. Follow-up t-tests revealed that the ASDANX (n=30) group showed significantly increased brain activation relative to ASDONLY (n=40) in the left insula and left inferior frontal gyrus (IFG), right MFG, as well as bilateral inferior parietal lobule and temporal areas. ASDANX also displayed increased activation in the left insula, left IFG and posterior brain regions relative to ANXONLY (n=326).We also found an interaction between ASD traits and anxiety in a cluster encompassing right MTG, superior temporal gyrus and insula . Figure ANX>all other groups in the left IFG, insula and MFG). After controlling for the effects of depression, all results remained significant, except for one cluster in the ASDANX>ASDONLY comparison (activations in the left insula and left IFG no longer significant).All results remained significant after controlling for the effects of ODD, and we found two additional clusters in the ASD-by-anxiety interaction  showed lower activation in the right superior and medial frontal gyri relative to youth with low ASD traits (n=1523). Irrespective of ASD-trait severity, participants with anxiety symptoms (n=396) showed decreased activation in the following regions following negative feedback: bilateral caudate, bilateral IFG, right SFG, left MFG, left inferior parietal lobule and left MTG.We found a main effect of ASD-trait severity and a main effect of anxiety . ParticiONLY  had significantly decreased brain activation in bilateral MFG and IFG extending to the anterior cingulate, left precentral gyrus, and corpus callosum extending to the left caudate compared to ASDONLY (n=43). ASDANX also displayed decreased activation in bilateral caudate and putamen relative to ANXONLY (n=361).We also found an interaction between ASD traits and anxiety severity in the right caudate and putamen, prefrontal regions and left MTG. While anxiety did not affect brain activations in these regions in youth with low ASD traits, young people with ASD traits and anxiety showed markedly lower activations compared to ASDONLY . Follow-k=120, PFWE=0.084; left MFG and IFG k=114, PFWE=0.104; left caudate and sgACC k=121, PFWE=0.081). The main effect of ASD was just below threshold for significance . The ASDANX< ANXONLYt-test remained significant, but 3/4 clusters in the ASDANX<ASDONLY comparison lost significance .After controlling for the effects of ODD, the ASD-by-anxiety interaction remained significant, and we found an additional cluster encompassing the left caudate and left IFG. The main effect of anxiety remained significant in three out of six previously found clusters . We also found two additional clusters encompassing the left IFG, left caudate and left putamen in the ASD-by-anxiety interaction.All results remained significant after controlling for the effects of depression, except for one cluster in the ASDThe results were broadly consistent with anxiety analyses and are described in detail in n=81) displayed increased activation in the bilateral thalamus and pallidum, as well as right putamen, compared to youth with low ASD traits . No main effect of anxiety was found.Across the whole sample, we found a main effect of ASD-trait severity. Youth with high ASD traits : MTG, insula, Brodmann area (BA) 32 , caudate, thalamus and medial frontal gyrus .medFGright=62.33, 95% CI [1.46−2668.54], P=0.031; ORBA32right=33.22, 95% CI [1.47−750.36], P=0.028; High ASD traits: In participants with high ASD traits, increased activations in the right medFG and right BA 32 during reward anticipation were associated with a higher likelihood of anxiety at follow-up, with baseline anxiety and ASD traits included in the model (ORLow ASD traits: None of the ROIs significantly predicted new-onset anxiety in participants with low ASD traits.P=0.024). Likewise, the interaction between ASD traits and right BA 32 significantly predicted future anxiety , P=0.029).Interaction effects across the whole sample: The interaction term between ASD traits and right medFG was a significant predictor of new-onset anxiety at follow-up , No significant results were found for the remaining ROIs.None of the ROIs we tested  predicted dichotomous anxiety status at follow-up in either ASD traits group.We found independent effects of ASD traits and anxiety on neural correlates of reward processing. We also found interaction effects whereby youth with combined ASD traits and anxiety showed distinctively high right MTG and insula activation when anticipating reward, and low prefrontal activation during negative feedback. Moreover, in participants with ASD traits, brain activation patterns during reward anticipation predicted new onset of anxiety 2 years later.61 Participants with ASD traits may attach less salience to rewards, consistent with previous studies showing reduced reward sensitivity in ASD youth.36 During negative feedback, youth with ASD traits showed reduced activation in the right medial PFC compared to those with low ASD traits. Previous studies in healthy adults showed that while obtaining an expected reward is associated with an increase in medial PFC activation, reward omission leads to decreased activation in this region.63 This functional modulation was proposed to reflect medial PFC's role in tracking rewarding outcomes. In this context, our results may indicate that participants with high ASD traits find the lack of expected reward relatively more punishing or aversive64 than those with low ASD traits. Combined with increased activation in reward-sensitive structures 65 in participants with high ASD traits following positive feedback, our results suggest that inadequate salience detection during reward anticipation may have led to exaggerated responses to both positive and negative reward outcomes.During both reward anticipation and negative feedback, we observed attenuated BOLD activation in prefrontal regions in participants with high compared to low ASD traits. When anticipating reward, participants with high ASD traits showed reduced activation in dorsal ACC and right dorsal prefrontal cortex (PFC) (BA 9), regions involved in working memory, cognitive salience detection and monitoring of reward-based behavioral responses.66 a region implicated in cognitive control via inhibition of prepotent behavioral responses.69 Increased activation in right MFG during anticipation suggests that participants with higher anxiety symptoms required more cognitive effort to maintain stimulus−reward representations active when faced with competing events.68 This is consistent with previous studies where anxious adolescents showed more emotional interference70 and heightened concern about making errors23 during reward processing compared to controls. However, we did not find the expected pattern of enhanced striatal activation during the anticipation of reward, which occurs specifically in social anxiety disorder.72 This could relate to the low rate of social anxiety in our sample. Conversely to reward anticipation, following negative reward feedback, anxious participants displayed reduced activation in the lateral PFC  and bilateral caudate.Participants with anxiety showed increased activation in the right MFG during reward anticipation, but decreased right MFG activation following negative feedback, compared to participants without anxiety. MFG is part of the lateral PFC,73 particularly in anticipating and predicting salience of aversive events,77 as well as in interoceptive processing.80 Interestingly, interoceptive prediction errors have been proposed to play a role in mood and anxiety disorders81 and theory of mind.82 Future studies should test directly whether the distinct pattern of activations observed during reward anticipation in our ‘combined' group is related to interoceptive prediction errors, a possible etiological mechanism underlying the comorbidity between ASD and anxiety. Reduced right-sided caudate, putamen and medial PFC (BA 10) activation during negative feedback suggests that participants in the combined group may have found not receiving the reward more aversive than other participants, similarly to reward anticipation. We also found reduced lateral PFC activation in the combined group following negative feedback. Interestingly, some but not all activation patterns that characterize the interaction effect were also found in the main effect of ASD traits (BA 10) and anxiety , suggesting shared and unique neural substrates of negative reward feedback in youth with combined ASD traits and anxiety.The key aim of this study was to examine the interplay of ASD traits and anxiety symptoms during reward processing. We explored interaction effects to test whether the co-occurrence of ASD traits and anxiety was associated with a quantitative change in, or a qualitatively unique pattern of, reward-related brain activations. We found that youth with combined ASD traits and anxiety showed a unique pattern of high right insula activation during reward anticipation, as well as increased right MTG activation during anticipation and markedly low right-sided caudate, putamen, medial and lateral PFC activation during negative feedback. These effects remained significant after controlling for the effects of possible confounders (depression and ODD symptoms). Interestingly, insula hyperactivation was not observed in any of the main effects above, suggesting that youth with ASD traits and anxiety may display a qualitatively different pattern of neural activations during reward anticipation. The insula is implicated in ‘aversion-related' reward processingIn participants with high but not low ASD traits, increased right medFG and right dorsal cingulate activations during reward anticipation were associated with increased likelihood of anxiety symptoms 2 years later. Predictions were significant after controlling for baseline anxiety, showing that MRI can predict new onset of anxiety problems.83 and in those with comorbid ADHD and anxiety.86 In addition, a specific biomarker of anxiety in ASD could aid differential diagnosis in cases where comorbid anxiety may be phenomenologically indistinguishable from ASD.87Our findings suggest that the presence of combined ASD traits and anxiety is associated with both a quantitatively potentiated neural response to negative reward feedback  as well as emergence of qualitatively different neural correlates during reward anticipation (activation in the right insula found exclusively in the interaction). This suggests that shared and distinct etiological mechanisms might be involved in the comorbidity between ASD and anxiety, and, if replicated, carries important clinical implications. If the co-occurrence of anxiety in ASD is underpinned by a distinct pathophysiological mechanism, the comorbid group may need to be recognized as a distinct nosological category and be researched in its own right. Moreover, it is possible that medication response in this group is also different. We know already from ADHD literature that the effectiveness of methylphenidate is reduced in some youth with ASD5Second, although MRI findings predicted only a small portion of the variance in new onset of anxiety at follow-up, brain activations were a significant predictor that could be used in establishing useful biomarkers of anxiety risk in youth with ASD traits. Our design strengthens the implication that the pattern of right-sided medFG and dorsal cingulate activations during reward processing is not merely a marker of anxiety, but may reflect an underlying mechanism by which young people with ASD traits become anxious. Ultimately, finding an MRI biomarker of anxiety in ASD has a potential of guiding treatment interventions and measuring treatment response, which is especially useful in cases where the value of clinical interview is limited due to social communication difficulties.88 Future studies should investigate whether reward-processing deficits can explain the presence of executive function deficits in ASD,89 and explore the role of comorbid anxiety in the process.Third, recent evidence suggests that disrupted processing of reward may lead to decision-making problems.90 holds in youth with ASD traits. Third, while our a priori choice of a cluster-forming threshold of P<0.01 at the voxel level is in line with previous reward-processing fMRI studies in adolescents that used the same91 or more lenient92 voxel-wise thresholds, and a large sample size is likely to limit the rate of false positives,41 it is still important that our results are replicated in an independent sample. Finally, the relative contribution of anxiety and ASD-specific difficulties to reward processing in youth with a clinical diagnosis of ASD remains to be studied.Although we investigated both anticipation and feedback phases of reward processing, task learning was performed outside of the scanner; therefore it was not possible to study the neural correlates of stimulus−reward learning. Second, due to sample size limitations we did not distinguish between different types of anxiety disorders. Future studies should test whether the differential impact of specific types of anxiety on reward processing, seen in typically developing youth,In conclusion, over and above the independent effects of ASD traits and anxiety, we found qualitatively distinct and quantitatively potentiated neural correlates of reward processing in youth with combined anxiety and ASD traits. Future studies should assess whether the apparent co-occurrence of ASD and anxiety is associated with distinct etiological mechanisms.


Sex hormones have diverse immunomodulatory effects that may be involved in the pathogenesis of sepsis. However, the roles of serum sex hormones in predicting outcomes and the severity of organ dysfunction, especially acute kidney injury (AKI), in septic shock patients remains controversial. We prospectively enrolled 107 clinically diagnosed pneumonia-related septic shock patients and serum sex hormone levels were measured on the day of shock onset. The aim of the present study was to investigate the predictive values of serum sex hormones levels for 28-day mortality and organs dysfunction, especially AKI. Compared with survivors, serum levels of progesterone (p<0.001) and estradiol (p<0.001) were significantly elevated in non-survivors. In multivariate Cox regression analysis, serum level of estradiol >40 pg/mL (p = 0.047) and APACHE II score ≥25 (p = <0.001) were found to be independent predictors of day 28 mortality. Inclusion of estradiol levels further enhanced the ability of APACHE II scores to predict survival in patients with high mortality risk. A serum level of estradiol >40 pg/mL was also an independent predictor of concomitant AKI (p = 0.002) and correlated well with severity of renal dysfunction using RIFLE classification. Elevated serum estradiol levels also predicted the development of new AKI within 28 days of shock onset (p = 0.013). In conclusion, serum estradiol levels appear to have value in predicting 28-day mortality in septic shock patients. Increased serum estradiol levels are associated with higher severity of concomitant AKI and predict development of new AKI. Sepsis and septic shock involve dysregulated inflammatory responses caused by interaction between the host immune system and microorganisms. Despite recent progress in care, sepsis and septic shock remain associated with high morbidity and mortality Sex hormones have been reported to have regulatory effects on immune responses. Estradiol can induce the production of pro-inflammatory cytokines and macrophage activation Sepsis-related AKI is associated with increased mortality and morbidity in critically ill patients The study protocol was approved by the Taipei Veterans General Hospital Institutional Review Board, and the study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants or their authorized representatives before enrollment.3) or leukopenia (<4000/mm3), increased sputum production, and new infiltrates on plain chest films This was a prospective, observational study conducted in a referral medical center in Taipei, Taiwan. From January 2008 to December 2011, patients admitted to the medical intensive care unit (ICU) and respiratory ICU were screened for the presence of septic shock associated with pneumonia. Specifically, patients with a diagnosis of pneumonia complicated by septic shock that fulfilled the Surviving Sepsis Campaign criteria for septic shock were included Broad-spectrum antibiotics were administered within 1 hour of the onset of septic shock, which is the standard of care in the ICUs where the current study was conducted. The antibiotics were adjusted based on clinical responses and drug susceptibility profiles of bacterial cultures. In addition, all patients were given a physiological dose of corticosteroid  for refractory hypotension The development of new AKI within 28 days of enrollment was recorded. New AKI was defined as increased serum creatinine >1.5 times baseline, or GFR decrease >25% of the baseline value, or decreased urine output <0.5 ml/kg/h for 6 hours in patients without concomitant AKI on enrollment.Peripheral blood samples were collected within 24 hours after shock onset. Total serum estradiol and progesterone were measured using radioimmunoassay (RIA) kits . Serum testosterone was measured using a RIA kit .Comparisons of demographic characteristics were carried out using chi-squared or Fisher’s exact tests for categorical variables and two-tailed independent t-test or Mann-Whitney U test for continuous variables. A multivariate Cox proportional hazards regression model with forward stepwise selection procedures was used to identify the risk factors for 28-day mortality. Binary logistic regression analysis was performed to determine independent variables associated with the development of concomitant AKI. Age, gender, comorbitities, and serum sex hormones levels were included in univariate analysis. A p value of less than 0.1 in the univariate analysis was required for a variable to be entered into the multivariate analysis model.For survival analysis, patients were stratified into subgroups according to serum sex hormone levels. The Kaplan-Meier method was used to estimate survival time and the development of new AKI, and the log-rank test was used to compare mortality between subgroups of patients. Censored analysis was used because observation stopped after a patient was dead or was discharged from the hospital. Receiver operating characteristic (ROC) curves were constructed to determine the predictive abilities of sex hormone levels for survival and the presence of AKI. A p value of less than 0.05 was considered statistically significant for all tests. Statistical analysis was performed using a statistical software package .From January 2008 to December 2011, a total of 151 pneumonia-related septic shock patients were eligible for inclusion. The study profiles and reasons for exclusion are shown in Serum sex hormone levels were comparable between male and female patients (data not shown). When compared with survivors, non-survivors of pneumonia-related septic shock patients had higher progesterone levels (p<0.001), higher estradiol levels (p<0.001), but similar testosterone levels (p = 0.74) .Regarding mortality, ROC curves of day-1 serum sex hormone levels and APACHE II scores in predicting 28-day mortality were constructed and are shown in Kaplan-Meier survival curves categorized by the optimal cut-off points of serum sex hormone levels from the ROC curves are shown in Cox regression analyses including clinical factors, serum sex hormone levels and disease severities, which were represented by APACHE II scores, associated with mortality are shown in Associations between the presence of organ dysfunction, including AKI, ARDS, hematologic dysfunction and metabolic acidosis, and serum sex hormone levels are shown in Because of the observed close correlation between serum sex hormones and AKI, we further analyzed their predictive values for concomitant AKI. ROC curves of serum sex hormones in predicting the presence of concomitant AKI are shown in As our analyses demonstrated the strong association between concomitant AKI and serum estradiol levels, but not progesterone, we further evaluated the predictive value of serum estradiol for the development of new AKI. Among 49 patients who had no concomitant AKI on enrollment, AKI subsequently developed in 23 (46.9%) within 28 days after shock onset. As shown in In the present study, we found that serum estradiol and progesterone levels significantly increased in non-survivors of pneumonia-related septic shock patients. In multivariate cox regression model, only serum estradiol level was independent predictors for 28-day mortality. We also demonstrated the additive value of estradiol in combination with APACHE II scores for 28-day mortality prediction. Meanwhile, escalated serum estradiol levels correlated well with increased severity of sepsis-related AKI. In multivariate analysis, increased serum estradiol level was an independent factor associated with the presence of AKI on the first day of shock onset. Serum estradiol levels also predicted the development of new AKI within 28 days of shock onset. By contrast, there is no significant difference in testosterone levels regarding survival status and the presence of AKI.The diverse effects of sex hormones on immune reaction and inflammation have been described extensively in cellular and animal studies. Estrogen appears to exert immunomodulatory effects through increased secretion of cytokines and chemokines from inflammatory cells There are only a few reports evaluating serum sex hormone levels in patients with septic shock. One study demonstrated that higher levels of estradiol and estrone, but not of testosterone, were found in critically ill patients with sepsis and septic shock The source of increased estradiol concentration in patients with concomitant AKI remains uncertain. Peripheral aromatase has the ability to convert androgens into estrogens, and could be stimulated by stress Based on our findings, what’s the practical value of serum estradiol levels in the management of septic shock patients? Although inferior to APACHE II scores, we found that estradiol has the additive value in predicting mortality when combining with APACHE II scores. Moreover, we demonstrated that estradiol could be a novel marker to predict the development of new AKI in septic shock patients. For patients with high estradiol levels, clinicians should keep adequate fluid status, avoid nephrotoxic agents, close monitor renal function and consider early dialysis if the renal function starts to deteriorate. Meanwhile, the specific role of estradiol in the severity stratification of sepsis-related AKI also deserves further investigation.This study has several limitations worth noting. Only patients with pneumonia-related septic shock were enrolled, and most of them were relatively older with higher disease severity. The homogeneity of the patients reflects the characteristics of a tertiary medical center. Most of the enrolled patients were male, so the results might not hold true for female patients. Although middle-aged individuals were included, we did not enroll premenopausal women in order to avoid the confounding effects from menstruation. Meanwhile, since no differences in serum sex hormone levels were found between male and female patients in the present study, gender disparities in the older population studied might not be an issue. Finally, blood samples for sex hormone measurements were collected only on the first day of shock onset, limiting further evaluation of the changing patterns of sex hormone levels during the course of septic shock in predicting outcomes.In conclusion, serum estradiol levels determined within 24 hours after the onset of pneumonia-related septic shock are predictive of 28-day mortality in this patient population. Serum estradiol levels are associated with concomitant AKI and correlates well with its severity. Initial serum levels of estradiol, but not of progesterone or testosterone, also predict the development of new AKI within 28 days of shock onset. Further studies are warranted to dissect the specific role of estradiol in sepsis-related AKI and the potential of sex hormone specific therapies in the treatment of septic shock.Table S1Criteria for organ dysfunction.(DOC)Click here for additional data file.


The purpose of this study was to investigate the utility and limitations of various imaging modalities in the noninvasive assessment of a novel compact hemodialyzer under development for renal replacement therapy, with specific aim towards monitoring its functional performance.The prototype is a 4×3×6 cm aluminum cartridge housing “blood” and “dialysate” flow paths arranged in parallel. A sheet of semipermeable silicon nanopore membranes forms the blood-dialysate interface, allowing passage of small molecules. Blood flow was simulated using a peristaltic pump to instill iodinated contrast through the blood compartment, while de-ionized water was instilled through the dialysate compartment at a matched rate in the countercurrent direction. Images were acquired under these flow conditions using multi-detector computed tomography (MDCT), fluoroscopy, high-resolution quantitative computed tomography (HR-QCT), and magnetic resonance imaging (MRI). MDCT was used to monitor contrast diffusion efficiency by plotting contrast density as a function of position along the path of flow through the cartridge during steady state infusion at 1 and 20 mL/min. Both linear and exponential regressions were used to model contrast decay along the flow path.Both linear and exponential models of contrast decay appeared to be reasonable approximations, yielding similar results for contrast diffusion during a single pass through the cartridge. There was no measurable difference in contrast diffusion when comparing 1 mL/min and 20 mL/min flow rates. Fluoroscopy allowed a gross qualitative assessment of flow within the device, and revealed flow inhomogeneity within the corner of the cartridge opposite the blood inlet port. MRI and HR-QCT were both severely limited due to the paramagnetic properties and high atomic number of the target material, respectively. During testing, we encountered several causes of device malfunction, including leak formation, trapped gas, and contrast-mediated nanopore clogging. We illustrate the imaging manifestations of each.Despite the inherent challenges in imaging a predominantly metallic device, some modalities show potential in the non-invasive assessment of a novel compact hemodialyzer. The approaches described here could potentially be translated to device evaluation in the implanted setting. End-stage renal disease (ESRD) is becoming increasingly common, in part due to the rising prevalence of hypertension and diabetes . Kidney 2; pore size: 7 nm×4 μm), which allow the diffusion of small solutes between the chambers. Membranes were polyethylene glycol (PEG) coated, which will be necessary for biocompatibility in future in vivo studies [The prototype  consists studies . The othThe device components were assembled using brass screws and aluminum washers, with silicone glue sealant. The membranes were fixed within the titanium mounting plate using a silicone-based organic polymer polydimethylsiloxane (PDMS). Device assembly and tubing connections and exchanges were performed during submersion in de-ionized water in attempt to exclude any air bubbles from within the device.Flow rates were equal and in opposite directions within the blood and dialysate compartments, respectively (countercurrent exchange). Iodinated contrast  in various dilutions was instilled via the blood ports, while de-ionized water was instilled via the dialysate ports. Flow was powered using a peristaltic pump , coupled to size LS-14 Precision silicone tubing . Flow rates were validated on-site to within 5% accuracy. All specified rates refer to flow within each compartment.X-ray fluoroscopy was performed using the Innova 4100 Angiographic Imaging System . Following a pre-contrast spot image, cine images were acquired in two projections during a 90-second dynamic infusion of Omnipaque 350 via the blood inlet port at a rate of 20 mL/min. Sequences were viewed using a PACS workstation to qualitatively assess flow patterns.Diffusion data were obtained using a 64-detector MDCT scanner . Images were helically acquired at 140 kV and 250mA. The image plane of acquisition was chosen such that the flow paths were displayed in cross-section  as a proxy for contrast concentration, taking advantage of the direct linear relationship between the two variables . We plotA sequence of four MDCT diffusion experiments (designated I through IV) was performed to investigate the hypothesis that clogging of the membrane pores may occur at high contrast concentrations. Each sequential experiment consisted of a non-contrast acquisition followed by two post-contrast acquisitions at steady state flow rates of 1 mL/min (minimum deliverable rate) and 20 mL/min (maximum rate not exceeding an estimated pressure of 1 psi within the system), respectively. All studies were conducted at room temperature (21°C) using iodinated contrast solutions ranging in strength from pure Omnipaque 350 to a 1:1 solution of Omnipaque 350 and deionized water. Intensity of cartridge flushing was progressively escalated between experiments, ranging from no flushing between Experiments I and II, to flushing for 24 hours at 38°C between experiments III and IV, as depicted in .MR imaging was attempted to determine feasibility on a 3-Tesla GE 15.4 MRI . The device was positioned within a head coil and surrounded by saline bags, while standard T2 FSE and T1 spin-echo sequences were acquired.Imaging of the entire cartridge was attempted to determine feasibility using the Xtreme CT HR-pQCT . Images were acquired at the maximum attainable tube voltage of 60 kV.Under SEM, we examined both a naive membrane and a contrast-exposed membrane . Specimens were attached to aluminum specimen blocks with adhesive carbon tabs, sputter coated with Palladium-Gold, and examined in a Nikon/JEOL Neoscope SEM. An accelerating voltage of 10 or 15 kV was applied and the secondary electron signal was recorded. A second observation was made after the samples were attached at a 45-degree angle with colloidal silver paste.We encountered two major limitations to MDCT imaging. For one, image quality suffered from beam-hardening and photon starvation due to the high x-ray attenuating properties of the metallic device components. There was significant improvement in image quality with increasing tube voltage, ranging between 60 and 140 kV . AnotherDespite its limitations, MDCT provided a semi-quantitative assessment of contrast diffusion by measuring the decrement in contrast density along the flow path through the cartridge . DiffusiEstimated diffusion values for Experiments I through IV are summarized in Fluoroscopy provided a gross visual assessment of contrast flow within the device. Cine images demonstrated flow inhomogeneity, with early preferential accumulation of contrast in the corner of the device across from the inlet port, suggesting recirculation in this region . As woulOn several occasions, a cause of device malfunction was depicted radiographically, either confirming a suspected abnormality or representing an incidental finding. Several examples include the following.To varying degrees, small pockets of gas were evident during imaging, either within the blood compartment, dialysate compartment, or both . The locFollowing initial device assembly, MDCT imaging during instillation of non-dilute contrast demonstrated dense fluid puddling beneath the cartridge, which progressively increased in density over serial acquisitions . This fiOn several occasions, a communication developed between the blood and dialysate compartments. As with the external leak, this occurred using non-dilute contrast solution. Based on our experience with the device, it appears that a rapid change in pressure within the cartridge (as occurs with abrupt initiation of flow) may result in fracture of the membranes units. This problem was best shown by fluoroscopy, which demonstrated immediate filling of the dialysate chamber with contrast instilled via the blood compartment. This occurred too briskly and was too dense to be the result of contrast diffusion. The communication appeared localized to a single point near the proximal end of the cartridge . An inteOn one occasion, forceful impact to the device resulted in a new large communication between the blood and dialysate compartments, manifesting as coupling of flow between compartments . Based on this behavior, major damage to the internal structure of the device was suspected, and a non-contrast CT was obtained for further evaluation. This demonstrated comminuted full-thickness fractures of the internal silicon plates, with numerous displaced fragments . The devAs described above, exposure to concentrated iodinated contrast material resulted in clogging of the membrane nanopores, with an associated decline in function.The present study was motivated by the anticipated need to develop non-invasive means for assessing a novel portable hemodialysis device. We investigated various imaging modalities in this capacity, disclosing various device failure modes in the process. The most promising modality was MDCT, which not only provided detailed structural information, but also allowed a functional assessment with regard to membrane diffusion. The methods described here could prove valuable in the implanted setting for monitoring device function.Imaging is well established in detecting certain complications related to medical implants. For example, fluoroscopy and CT have demonstrated leaks from intrathecal medication pumps . SimilarIt is worth noting that leakage may be related to the viscosity of the fluid used. We frequently used 1:1 dilute Omnipaque 350 at room temperature, the viscosity of which is approximately 3.1 cp, closely approximating that of whole blood at body temperature .It is unclear how to best model the contrast diffusion kinetics from our MDCT data. Thus, we applied both linear and exponential regression models, recognizing that both represent imperfect approximations. Given this uncertainty, our results should not be interpreted as an exact quantification of diffusion, but rather as relative values illustrating trends in diffusion over time. For example, we were able to detect decreasing diffusion associated with contrast-mediated membrane pore clogging.There was no penalty in terms of single-pass diffusion at 20 mL/min compared to 1 mL/min, suggesting rapid diffusion across the membranes, which is not rate-limited in this range of flow rates. Importantly, our results pertain to the small uncharged molecule iohexol , and are likely not generalizable to solutes with different properties. Diffusivity of iohexol cannot be determined, as clearance was not calculated in this study.A qualitative fluoroscopic assessment of contrast flow within the device revealed early preferential accumulation of contrast in the corner of the device across from the contrast inlet port, suggesting recirculation. If future device modifications were to achieve MRI compatibility, quantitative flow mapping and flow velocity measurements might be possible . This tyThis study has several limitations. For one, there were two interrelated variables in experimental sequence I through IV: contrast concentration and degree of cartridge flushing. With the present study design, it is not possible to separate their effects on the observed pore clogging, with both variables likely playing a role. Notably, our studies sed supra-physiologic contrast concentrations at room temperature. Further studies are necessary to determine to what degree, if any, pore clogging would be a factor using lower concentrations of contrast at body temperature, since it is known that the viscosity of iohexol varies linearly with temperature and quadratically with concentration .Imaging a predominantly metal device presented several inherent challenges. MRI, a potentially powerful tool in measuring flow, was ineffective due to overwhelming metallic susceptibility artifact. The device composition also posed a substantial challenge to imaging by MDCT, with the highly attenuating metallic components resulting in severe beam-hardening, limiting the sensitivity for the detection of subtle contrast differences. Density profiles were further degraded by superimposed periodic peaks representing partial volume averaging from the adjacent membrane units alternating with intervening metal struts, introducing error in our calculated density gradients. In order to overcome these factors, we used high contrast concentrations, which in turn promoted pore clogging.Image quality was significantly improved by increasing tube voltage to 140 kV, the maximum capability of our conventional MDCT scanner, which suggests a possible role for future studies using megavoltage CT. One of numerous metal artifact suppression algorithms might also be considered, although could result in data distortion in ways that are difficult to predict, and would therefore require validation with an existing imaging model. Imaging quality will likely be most improved by varying the constituent materials of the device within structural constraints.In summary, this study outlines our initial experience using various imaging approaches in the evaluation of a portable hemodialysis device. Despite the inherent challenges in imaging a predominantly metallic device, several modalities show potential for non-invasive structural and functional assessment. The approaches described here could potentially be translated to device evaluation in the implanted setting.


The study aimed to investigate sleep patterns, sleep disturbances and possible factors that are associated with sleep disturbances among children with FMF.Children's Sleep Habits Questionnaire was performed. It is a parent-report questionnaire assessing the typical sleep patterns of children. It includes 33 items measuring sleep disturbances  and 3 three items collecting information about bedtime, wake-up time and sleep duration over a "typical" recent week. A total score of ≥41 defines "clinically significant sleep disturbance".Forty six FMF patients and 80 age- and sex-matched healthy children were enrolled in the study Table . The patThe total sleep scores of the patients with FMF were significantly higher than the control group. Total sleep duration were similar between 2 groups. The comparison of subscale scores were given in table. Gender and age had no effect on total sleep scores in both groups. There was not a significant corelation between the total sleep score and disease duration, dose of colchicine, disease severity score, number of attacks in the last year, and serum C-reactive protein level in FMF patients. Besides, the patients with exercise-induced myalgia (n = 21) had significantly higher sleep scores than the patients without (n = 25) .This is the first study investigating sleep patterns, sleep disturbances and possible factors that are associated with sleep disturbances among children with FMF. The results of this study suggested that exercise-induced myalgia might contribute to sleep disturbances in FMF as well as ongoing subclinical inflammation.None declared.