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Abstract: Backgrounds & Aims: Individualized tacrolimus treatment can improve drug safety and efficacy. In this study, we aimed to investigate the association of donor and recipient small ubiquitin‐like modifier 4 (SUMO4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism. Methods: A total of 297 liver transplant patients were enrolled in the study. CYP3A5 rs776746 and SUMO4 rs237025 were genotyped using TaqMan SNPs assays. The activity of nuclear factor‐kB (NF‐kB) was evaluated by luciferase assay. The expressions of CYP3A5 were detected by qRT‐PCR and western blotting. Results: Tacrolimus C/D ratios was significantly lower for donor SUMO4 rs237025 AA carriers than AG/GG carriers at weeks 1, 2, 3. In multivariate analysis, donor and recipient CYP3A5 rs776747, donor SUMO4 rs237025 and total bilirubin were independent predictors of tacrolimus C/D ratios in the early post‐transplantation period both in Cohort A and Cohort B. When combined donor CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes, tacrolimus C/D ratios was highly significant at all investigated time points within the four groups. CYP3A5 mRNA expression in liver tissues was significantly higher for AA carriers than AG/GG patients under inflammatory stimuli after liver transplantation (LT). Furthermore, we demonstrated that SUMO4 rs237025 G allele could increase NF‐κB transcriptional activity under inflammatory condition. And activation of NF‐kB suppressed the expression of pregnane X receptor (PXR)‐mediated CYP3A5 gene. Conclusions: Donor SUMO4 rs237025 genetic variant was associated with higher Tac C/D ratios in the early period after LT, which might be related to the down‐regulation of CYP3A5 enzyme through the NF‐kB signalling pathway. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH.Experimental Approach: NASH was induced in mice by feeding a choline-deficient, l-amino acid-defined, high-fat diet. These mice received either placebo or the sGC stimulator IW-1973 at two different doses (1 and 3 mg·kg-1 ·day-1 ) for 9 weeks. IW-1973 was also tested in high-fat diet (HFD)-induced obese mice. Steatosis, inflammation and fibrosis were assessed by Oil Red O, haematoxylin-eosin, Masson's trichrome, Sirius Red, F4/80 and α-smooth muscle actin staining. mRNA expression was assessed by quantitative PCR. Levels of IW-1973, cytokines and cGMP were determined by LC-MS/MS, Luminex and enzyme immunoassay respectively.Key Results: Mice with NASH showed reduced cGMP levels and sGC expression, increased steatosis, inflammation, fibrosis, TNF-α and MCP-1 levels and up-regulated collagen types I α1 and α2, MMP2, TGF-β1 and tissue metallopeptidase inhibitor 1 expression. IW-1973 restored hepatic cGMP levels and sGC expression resulting in a dose-dependent reduction of hepatic inflammation and fibrosis. IW-1973 levels were ≈40-fold higher in liver tissue than in plasma. IW-1973 also reduced hepatic steatosis and adipocyte hypertrophy secondary to enhanced autophagy in HFD-induced obese mice.Conclusions and Implications: Our data indicate that sGC stimulation prevents hepatic steatosis, inflammation and fibrosis in experimental NASH. These findings warrant further evaluation of IW-1973 in the clinical setting. [ABSTRACT FROM AUTHOR]

Hypoalbuminaemia has been previously described to predict worse nonrelapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo-HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft-versushost disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18-75) years, who underwent an allo-HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow-up for all surviving patients was 26 (3-55) months. Two-year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64-76%) vs. 49% (95% CI = 42-56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1-year posttransplantation [6% (95% CI = 3-10%) vs. 25% (95% CI = 20-32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence linking low blood vitamin D concentration to numerous diseases in people and in dogs. Vitamin D influences cellular function by signaling through the vitamin D receptor (VDR). Little is known about which non‐skeletal tissues express the VDR or how inflammation influences its expression in the dog. Objectives: To define which non‐skeletal canine tissues express the VDR and to investigate expression in inflamed small intestine. Animals: Thirteen non‐skeletal tissues were collected prospectively from 6 control dogs. Thirty‐five dogs diagnosed with a chronic enteropathy (CE) and 24 control dogs were prospectively enrolled and duodenal biopsies were evaluated for VDR expression. Methods: Prospective; blinded assessment of canine intestinal VDR. Dogs with CE were included once other identifiable causes of intestinal disease were excluded. Age matched controls were included with no intestinal clinical signs. VDR expression was assessed immunohistochemically in all samples, using a Rat IgG VDR monoclonal antibody. Quantitative real‐time polymerase chain reaction (qPCR) was also used for duodenal biopsies. Results: VDR expression as assessed by immunohistochemistry (IHC) was highest in the kidney, duodenum, skin, ileum and spleen, and weak in the colon, heart, lymph node, liver, lung, and ovary. Gastric and testicular tissue did not express the VDR. There was no statistical difference in duodenal VDR expression between the 24 healthy dogs and 34 dogs with CE when quantified by either qPCR (P = 0.87) or IHC (P = 0.099). Conclusions and Clinical Importance: The lack of down regulation of VDR expression in inflamed intestine contrasts with previous studies in humans. Our findings support future studies to investigate whether vitamin D and its analogues can be used to modulate intestinal inflammation in the dog. [ABSTRACT FROM AUTHOR]

Abstract: Actinic keratoses (AK) arise on sun‐exposed regions of the skin. If left untreated, AK may progress to invasive squamous cell carcinoma (SCC), although the rate of progression is low. A practical treatment algorithm for the treatment of AK in standard situations has been published by the AKTeam™ expert panel. However, management of particular situations of AK with increasing/higher carcinoma risk or AK progressing into carcinomas with increased aggressiveness due to their anatomical location (risky areas), or in patients with an increased risk of SCC requires further discussion. These include AK on the dorsal hands, forearms, legs, periorbital region, eyelids, ears, or lips, and organ transplant recipients, patients undergoing treatment with carcinogenic agents and patients with chronic lymphocytic leukaemia. The main objective was to propose therapeutic strategies for the treatment of AK located in risky areas and in patients with more invasive/aggressive lesions and a higher risk of progression to SCC. A systematic review of the literature was initially performed, and results were discussed by the experts to propose best management practices in specific situations. Finally, adapted management strategies for AK occurring in risky areas and in high‐risk patients are presented, taking into account the experts’ own clinical experience and current guidelines. In most of these ‘at‐risk’ situations, patients can be treated according to the AKTeam™ treatment algorithm. Difficult‐to‐treat lesions should be treated more aggressively due to their higher risk of transformation. For patients with skin that is highly susceptible to actinic damage, monitoring and sun protection strategies are mandatory, and patients should undergo more regular follow‐up. Further assessment of newer therapies in clinical trials is necessary to determine optimal treatment conditions. This expert consensus provides guidance for the management of AK in risky body sites and in patients with an increasing/higher risk for SCCs. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Surgery and other non‐pharmacological treatments such as sacral nerve stimulation are used for the treatment of difficult‐to‐treat chronic constipation. Novel pharmacological therapeutic agents are also being introduced. To evaluate the efficacy of these treatments, it is imperative to have a consistent definition of pharmacologically refractory constipation. A systematic review of studies on refractory, difficult‐to‐treat or surgically treated constipation was carried out to determine the criteria that various authors used to define this group of patients. Methods: A systematic review was performed for literature published from June 2005 to June 2015 using PubMed, Cochrane, and Scopus databases, as well as manual searches. Studies on patients with refractory or intractable constipation were extracted. Criteria used for defining refractory constipation, as well as pharmacological agents tried including dosage, frequency, and duration, were reviewed. Results: Sixty‐one studies were included in this review. Forty‐eight involved surgical treatment of constipation, while 13 examined non‐surgical therapies for refractory constipation. There is no generally accepted definition of refractory constipation. Authors consider constipation to be refractory when response to management is suboptimal, but there is no consensus on the choice of drug, order of usage, and dosage or treatment duration. Prior medical therapy was not mentioned at all in five studies. Conclusions: There is need for a detailed definition of pharmacologically refractory constipation before submitting patients to invasive treatments and to evaluate new pharmacological agents. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Secondary loss of response to adalimumab (ADA‐LOR) commonly occurs in patients with Crohn's disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA‐LOR in adult CD patients. Methods: Patients were divided into either an ED (≥900 kcal/day) or a non‐ED group (<900 kcal/day). Cumulative non‐ADA‐LOR rates were compared between groups. The effects of ED intake to reduce ADA‐LOR were also assessed in antitumor necrosis factor‐alpha (TNF‐α)‐naïve and infliximab (IFX)‐intolerant or refractory CD patients. Serum ADA and TNF‐α levels were measured. Results: We enrolled 117 CD patients into the ED (n = 25) or non‐ED (n = 92) groups. Although the cumulative non‐ADA‐LOR rate was higher in the ED group than in the non‐ED group, ED intake was not an independent reducing factor for ADA‐LOR (adjusted hazard ratio = 0.725; 95% confidence interval: 0.448–1.180; P = 0.196) in all patients. ED intake was significantly more effective in reducing ADA‐LOR in IFX‐intolerant or refractory patients than in anti‐TNF‐α‐naïve patients in a dose‐related manner (P for interaction <0.20). Serum ADA levels did not differ between the groups. Serum TNF‐α levels were significantly lower in the ED group than in the non‐ED group at week 28 (P = 0.044) and week 52 (P = 0.043). Conclusions: Concomitant ED therapy reduced ADA‐LOR in IFX‐intolerant or refractory patients in a dose‐related manner. Reductions in the TNF‐α levels by concomitant ED intake may contribute to reduce ADA‐LOR in CD patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the outcomes 1 year and longer following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a large series of patients treated over a 5-year period since introduction of this novel technique.Methods: Surgical outcomes of a consecutive series of 58 patients with mesial temporal lobe epilepsy who underwent the surgery at our institution with at least 12 months of follow-up were retrospectively evaluated. A subgroup analysis was performed comparing patients with and without mesial temporal sclerosis.Results: One year following stereotactic laser amygdalohippocampotomy, 53.4% (95% confidence interval [CI] = 40.8-65.7%) of all patients were free of disabling seizures (Engel I). Three of 9 patients became seizure-free following repeat ablation. Subgroup analysis showed that 60.5% (95% CI = 45.6-73.7%) of patients with mesial temporal sclerosis were free of disabling seizures as compared to 33.3% (95% CI = 15.0-58.5%) of patients without mesial temporal sclerosis. Quality of Life in Epilepsy-31 scores significantly improved at the group level, few procedure-related complications were observed, and verbal memory outcome was better than historical open resection data.Interpretation: In an unselected consecutive series of patients, stereotactic laser amygdalohippocampotomy yielded seizure-free rates for patients with mesial temporal lobe epilepsy lower than, but comparable to, the outcomes typically associated with open temporal lobe surgery. Analogous to results from open surgery, patients without mesial temporal sclerosis fared less well. This novel procedure is an effective minimally invasive alternative to resective surgery. In the minority of patients not free of disabling seizures, laser ablation presents no barrier to additional open surgery. Ann Neurol 2018;83:575-587. [ABSTRACT FROM AUTHOR]

Abstract: In this article, I describe the processes through which patients diagnosed with ‘morbid obesity’ become active subjects through undergoing obesity surgery and an empowerment lifestyle programme in a Dutch obesity clinic. Following work in actor‐network theory and material semiotics that complicates the distinction between active and passive subjects, I trace how agency is configured and re‐distributed throughout the treatment trajectory. In the clinic's elaborate care assemblage – consisting of dieticians, exercise coaches and psychologists – the person is not only actively involved in his/her own change, the subject of intervention is the self as ‘actor’: his/her material constitution, inclinations and feelings. The empirical examples reveal that a self becomes capable of self‐care only after a costly and laborious conditioning through which patients are completely transformed. In this work, the changed body, implying a new, potentially disruptive reality that patients must learn to cope with, is pivotal to what the patient can do and become. Rather than striving to be disembodied, self‐contained liberal subjects that make sensible decisions for their body, patients become empowered through submission and attachment and by arranging support. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate elastic distraction surgical procedures performed on patients with syndromic craniosynostosis using cephalometric analyses.Methods: Eleven patients who underwent surgical midfacial advancement were divided into three groups: G1 - monobloc frontofacial; G2 - Le Fort III; and G3 - high-level Le Fort I. The cephalometric analyses were manually created through cephalometric radiographs of each patient: T1 - preoperative; T2 - 6 months postoperatively; and T3 - 12 months postoperatively. The cephalometric landmark points were A and O. The distances between preoperative and postoperative tracings were measured.Results: Point A advanced with no significant relapse 12 months after surgery. Point O advanced with a significant relapse rate of 28.5% postoperatively (p = 0.019). The vertical movement of points A and O increased by 40.6% (p = 0.033) and 38.8% (p = 0.032), respectively. There were no significant statistical differences between the assessed surgical techniques and syndromes with regard to midfacial advancement.Conclusion: Point O has presented statistically significant relapse only in horizontal movement after 12 months. The cephalometric analysis performed in the present study only suggested no differences between the studied surgical techniques and syndromes with regard to midfacial advancement in syndromic craniosynostosis. [ABSTRACT FROM AUTHOR]

Aims: Myiasis is a disease caused by the invasion of tissues by larvae of flies. The aim of this study was to carry out a review of reported cases of oral and maxillofacial myiasis in older adults and to show a case report of oral myiasis in a 95-year-old frail man with severe Alzheimer's disease from Brazil.Methods and Results: Between 1988 and 2017, 35 oral and maxillofacial myiasis cases were reported in older adults in English-language studies from PubMed and Lilacs databases.Conclusions: Oral and maxillofacial myiasis in older adults showed low incidence and good prognosis of cure, when there were no systemic complications. Weakness, frailty, dementia, oral lesions, labial incompetence, poor oral hygiene, and bad breath were associated with this disease in reported cases. Preferential therapy choices were debridement alone or combined with Ivermectin. In this case report, debridement and Ivermectin prescription was an effective therapy for an older adult with severe Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Summary: Background: The combination of sofosbuvir (SOF) plus an NS5A inhibitor for 12 weeks is highly efficacious in patients with chronic hepatitis C. As the costs of generic production of sofosbuvir and NS5A inhibitor are rapidly decreasing, the combination of these DAAs will be the standard treatment in most low‐ to middle‐income countries in the future. Aim: To identify key predictors of response that can be used to tailor treatment decisions. Methods: A cohort of 216 consecutive patients infected with HCV genotype 1 (1a: n = 57; 1b: n = 77), 2 (n = 4), 3 (n = 33) or 4 (n = 44) were treated with sofosbuvir (SOF) + daclatasvir (n = 176) or SOF + ledipasvir (n = 40) for 12 weeks. The viral kinetics was analysed using the biphasic model and the cure boundary was used to predict time to clear HCV. Results: The overall SVR rate was high (94.4%; n = 204), regardless of the time to viral suppression or low‐level viraemia at the end of treatment. The model‐based predicted HCV RNA levels at the end of treatment could not differentiate patients who did from those who did not achieve SVR. The presence of NS5A resistance‐associated substitutions [position 28 (OR = 70.3, P<.001) and/or 31 (OR = 61.6, P = .002)] at baseline was predictive of virological failure in cirrhotic patients but was not associated with on‐treatment viral kinetics. Conclusion: This real‐world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aim: Robust baseline predictors of interferon (IFN) response in HBeAg‐negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/ΔG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN‐treated CHB patients. Here we assessed whether IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN‐induced HBsAg clearance in CHB patients. Methods: We sequenced the IFNL4 gene on genomic DNA collected from 126 HBeAg‐negative CHB patients treated with IFN and followed up for a median of 11 (1‐23) years. Results: The 15‐year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes the IFNλ4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFNλ4‐S70 protein (39% vs 42%, P  =  .827). In contrast, these 81 patients, either not producing IFNλ4 or producing an impaired IFNλ4‐S70 protein, had a significantly higher 15‐year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFNλ4‐P70 (42% vs 11% P = .003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70‐20.9, P = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39‐0.83, P = .003). Conclusion: IFNL4 rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg‐negative CHB patients. [ABSTRACT FROM AUTHOR]

Abstract: Aim: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. Methods: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an ‘effective case’. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. Results: Thirty‐six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin‐8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1–17.6; P < 0.001), pre‐pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0–16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1–11.8; P = 0.028) were independent factors correlated with ID (< 2 days). Conclusion: Maintenance tocolysis may be effective in limited cases with mild intra‐amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF‐1 levels had suggested GH deficiency, while response to therapy indicated GH insensitivity. Molecular evaluation of the GH/IGF‐1 axis should be performed in these cases to improve diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We have tried to establish a safe and effective method to treat the peripelvic renal cyst combined with renal calculi. The key points are as follows: choose the appropriate target calyx; find the gap between cyst and renal pelvic; put a nephrostomy tube to stimulate the closing of cystic cavity. [ABSTRACT FROM AUTHOR]

Abstract: This article describes the author's development of an aesthetic approach to psychoanalytic psychotherapy of patients suffering from traumatic levels of grief by describing her experiences as a patient, a therapist, and a consultant to the design firm that partnered with the National September 11 Memorial and Museum. Using Aristotle's On Poetics as an inspiration, this article explores the ways dialogical storytelling creates a therapeutic “action‐plot” that transforms reversals of fortune. Attending to patients’ first‐person phenomenological experience (without attributing cause), therapists help them transform their losses by listening to their stories. Therapists dwell with them in uncertainties while marking time in regularly scheduled meetings; they accompany their patients on a journey while also orienting to their modes of travel. They simultaneously co‐construct tales of the journey, attentive to the poetic dimensions of sight, sound, and space that they encounter. In so doing, therapists serve not just guides and judges, but artists, bringing meanings to the trail. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oropharyngeal sensory impairment is a potential target to treat swallowing dysfunction in patients with oropharyngeal dysphagia (OD). Aim: To assess the therapeutic effect of stimulating oropharyngeal sensory afferents with TRPV1, TRPA1, or TRPM8 agonists vs increasing bolus viscosity in older and neurologic patients with OD by comparing four studies of similar experimental design. Methods: Swallow function of 142 older patients with impaired safety of swallow at nectar ([50‐350] mPa·s) viscosity was evaluated with videofluoroscopy (VFS) while treated with TRPV1 (150 μmol/L), TRPV1/A1 (150 μmol/L and 1 mmol/L), or TRPM8 (1 mmol/L or 10 mmol/L) agonists or modified starch (MS) at spoon thick viscosity (>1750 mPa·s). Results: TRPV1 stimulation with capsaicinoids reduced penetrations by 50%, pharyngeal residue by 80%, and LVC time by 24.38% and increased bolus velocity by 36.51%. TRPV1/A1 stimulation with piperine reduced penetrations by 56.32%, LVC time by 25.55% and increased bolus velocity by 23.63%. TRPM8 stimulation with menthol 1 mmol/L reduced penetrations by 37.5% while 10 mmol/L reduced LVC time by 18.44%. Thickeners reduced penetrations by 77.11%, but increased pharyngeal residue by 19.89%, delayed LVC by 41.73%, and reduced bolus velocity by 13.44%. Conclusion: Natural capsaicinoids have a stronger therapeutic effect on VFS signs and swallow response by stimulating TRPV1 than TRPV1/A1 or TRPM8 agonists. While TRP stimulants increased bolus velocity and reduced swallow response times, thickeners reduced bolus velocity and further delayed the swallow response. This study sets the bases to develop new pharmacologic strategies for older patients with OD, moving away from compensation toward the recovery of swallow function. [ABSTRACT FROM AUTHOR]

Abstract: Background: The role of immune activation in Functional Dyspepsia (FD) patients without previous infection is unclear. We compare the gastric and circulating brain‐derived neurotropic factor (BDNF), receptor potential vanilloid type (TRPV) families and various cytokines in FD patients. Methods: Consecutive adult FD patients (Rome III) with no recent history of gastroenteritis and asymptomatic healthy controls were recruited for upper endoscopy. Subjects with GERD and IBS as predominant symptoms, diabetes mellitus, current or previous Helicobacter pylori infection, psychiatric illness and recent use of NSAID or PPI were excluded. Corpus biopsies and serum samples were collected. Key Results: Forty three [M:F=8:35, mean age: 35.0 (9.3)] FD patients were compared with 23 healthy controls [M:F=8:15, mean age: 36.6 (10.2)]. FD patients had postprandial distress syndrome (PDS) as predominant sub‐type (PDS: 36, EPS: 2). There was no significant difference in the median inflammation score (FD:0 (0‐1) vs Control:0 (0‐1), P=.79). However, FD patients had significantly higher mRNA expression of TRPV1 (FD:0.014±0.007, Control:0.003±0.001, 4.6 fold, P=.02) and TRPV2 (FD:0.012±0.006, Control:0.003±0.001, 4 fold, P=.02) compared to controls. The serum (FD:258.0±12.3 ng ml−1, Control:319.7±18.1 ng ml−1, P<.01) and gastric BDNF mRNA (FD:0.06±0.008, Control:0.092±0.01, 0.65 fold, P=.02)levels significantly lower in FD patients. Secretion of cytokines (IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, G‐CSF, TGF‐β2, MCP‐1)was also highly correlated with dyspeptic symptoms in patients with FD. Conclusions & Inferences: Despite lacking gastric mucosal inflammation, up‐regulation of TRPV1 and TRPV2, down‐regulation of BDNF were observed in FD patients. These suggest that immune alteration may contribute to the pathogenesis of FD without any previous infection. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine the incidences and rates of progression of varying degrees of carotid stenosis that do not require intervention according to the Asymptomatic Carotid Atherosclerosis Study, the European Carotid Surgery Trial, and the North American Symptomatic Carotid Endarterectomy Trial, and from this information, to provide evidence‐based recommendations for follow‐up imaging. Methods: A retrospective review was performed of all carotid ultrasound examinations performed at a single institution from January 1995 through April 2015. Examinations following endarterectomy or stenting were excluded. Stenoses were classified by a modification of the criteria of Bluth et al (Radiographics 1988; 8:487–506). A Kaplan‐Meier survival analysis was performed for stenosis progression and to provide information for follow‐up recommendations. Results: Most of the carotid arteries (91.6%) reviewed for this study showed 1% to 39% stenosis. However, only 6.8% of carotid arteries with 1% to 39% stenosis progressed compared to 38.9% of carotid arteries with 40% to 59% stenosis. A table of evidence‐based follow‐up recommendations is provided for patients with varying levels of stenosis. Conclusions: We provide evidence‐based follow‐up recommendations for patients who have low degrees of carotid stenosis. Different degrees of carotid stenosis progress at different rates and therefore should be followed at different intervals. Additionally, the most patients in our database showed 1% to 39% stenosis and did not have any follow‐up imaging, suggesting that carotid ultrasound may not be overused for low degrees of stenosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: More than 30 million children are cared for across 5,000 U.S. emergency departments (EDs) each year. Most of these EDs are not facilities designed and operated solely for children. A Web‐based survey provided a national and state‐by‐state assessment of pediatric readiness and noted a national average score was 69 on a 100‐point scale. This survey noted wide variations in ED readiness with scores ranging from 61 in low‐pediatric‐volume EDs to 90 in the high‐pediatric‐volume EDs. Additionally, the mean score at the state level ranged from 57 (Wyoming) to 83 (Florida) and for individual EDs ranged from 22 to 100. The majority of prior efforts made to improve pediatric readiness have involved providing Web‐based resources and online toolkits. This article reports on the first year of a program that aimed to improve pediatric readiness across community hospitals in our state through in situ simulation‐based assessment facilitated by our academic medical center. The primary aim was to improve the pediatric readiness scores in the 10 participating hospitals. The secondary aim was to explore the correlation of simulation‐based performance of hospital teams with pediatric readiness scores. Methods: This interventional study measured the Pediatric Readiness Survey (PRS) prior to and after implementation of an improvement program. This program consisted of three components: 1) in situ simulations, 2) report‐outs, and 3) access to online pediatric readiness resources and content experts. The simulations were conducted in situ (in the ED resuscitation bay) by multiprofessional teams of doctors, nurses, respiratory therapists, and technicians. Simulations and debriefings were facilitated by an expert team from a pediatric academic medical center. Three scenarios were conducted for all teams and include: a 6‐month‐old with respiratory failure, an 8‐year‐old with diabetic ketoacidosis (DKA), and a 6‐month‐old with supraventricular tachycardia (SVT). A performance score was calculated for each scenario. The improvement of PRS was compared before and after the simulation program. The correlation of the simulation performance of each hospital and the PRS was calculated. Results: Forty‐one multiprofessional teams from 10 EDs in Indiana participated in the study, five were of medium pediatric volume and five were medium‐ to high‐volume EDs. The PRS significantly improved from the first to the second on‐site verification assessment (58.4 ± 4.8 to 74.7 ± 2.9, p = 0.009). Total adherence scores to scenario guidelines were 54.7, 56.4, and 62.4% in the respiratory failure, DKA, and SVT scenarios, respectively. We found no correlation between simulation performance and PRS scores. Medium ED pediatric volume significantly predicted higher PRS scores compared to medium‐high pediatric ED volume (β = 8.7; confidence interval = 0.72–16.8, p = 0.034). Conclusions: Our collaborative improvement program that involved simulation was associated with improvement in pediatric readiness scores in 10 EDs participating statewide. Future work will focus on further expanding of the network and establishing a national model for pediatric readiness improvement. [ABSTRACT FROM AUTHOR]

Background and purpose: Idiopathic intracranial hypertension (IIH) is characterized by abnormally elevated intracranial pressure (ICP) without identifiable etiology. Recently, however, a subset of patients with presumed IIH have been found with isolated internal jugular vein (IJV) stenosis in the absence of intracranial abnormalities. Methods: Fifteen consecutive patients were screened from 46 patients suspected as IIH and were finally confirmed as isolated IJV stenosis. The stenotic IJV was corrected with stenting when the trans‐stenotic mean pressure gradient (∆MPG) was equal to or higher than 5.44 cmH2O. Dynamic magnetic resonance venography, computed tomographic venography and digital subtraction angiography of the IJV, ∆MPG, ICP, Headache Impact Test 6 and the Frisén papilledema grade score before and after stenting were compared. Results: All the stenotic IJVs were corrected by stenting. ∆MPG decreased and the abnormal collateral veins disappeared or shrank immediately. Headache, tinnitus, papilledema and ICP were significantly ameliorated at 14 ± 3 days of follow‐up (all P < 0.01). At 12 ± 5.6 months of outpatient follow‐up, headache disappeared in 14 out of 15 patients (93.3%), visual impairments were recovered in 10 of 12 patients (83.3%) and tinnitus resolved in 10 out of 11 patients (90.9%). In 12 out of 15 cases, the Frisén papilledema grade scores declined to 1 (0–2). The stented IJVs in all 15 patients kept to sufficient blood flows on computed tomographic venography follow‐up without stenting‐related adverse events. Conclusions: Non‐thrombotic IJV stenosis may be a potential etiology of IIH. Stenting seems to be a promising option to address the issue of intracranial hypertension from the etiological level, particularly after medical treatment failure. [ABSTRACT FROM AUTHOR]

Objective: Development of the ‘Otology Questionnaire Amsterdam’ (OQUA), a patient reported outcome measure (PROM), measuring the severity and impact of ear complaints of patients visiting an ENT surgeon. Design: Multicenter, cross‐sectional study. Phase 1: qualitative research. In‐depth interviews (N = 16) to identify relevant types of ear complaints and to formulate items. Pilot study of the first and second draft of the OQUA (N = 32, N = 39). Phase 2: quantitative research. Field‐testing of the OQUA (N = 352). Item reduction based on inter‐item correlation, factor analysis and expert opinion. Setting: Two secondary and two tertiary ENT clinics. Participants: Patients over the age of sixteen visiting an ENT surgeon with an ear complaint. Main outcome measures: Phase 1: meaning units and frequency of selected descriptions. Phase 2: inter‐item correlation, factor loading and Cronbach's Alpha (α). Results: Phase 1: eight relevant types of ear complaints were identified: earache, pressure in ear, hearing loss, tinnitus, otorrhoea, itch, dizziness and loss of taste. Phase 2: factor analysis generated a factor ‘impact’ (α = 0.913). The current version of the OQUA consists of 34 items, covers eight types of ear complaints and consists of two constructs: complaints and impact. Conclusion: The OQUA is a generic, otologic PROM designed to evaluate the severity of ear complaints and their impact on patients lives. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To investigate the efficacy and safety of technetium‐99 conjugated with methylene diphosphonate (99Tc‐MDP, Yunke Pharmaceutical industry) in the treatment of rheumatoid arthritis (RA). Methods: A total of 120 patients with active RA were randomly divided into three groups: Group A (receiving oral meloxicam tablets); Group B (receiving intravenous drip of 99TC‐MDP); Group C (receiving combination treatment of intravenous drip of 99Tc‐MDP and oral meloxicam tablets). The main clinical and laboratory parameters were evaluated at baseline and after 14 days of therapy. Results: After 14 days of treatment, American College of Rheumatology 20 response was 15.62%, 34.04% and 48.78% in the three groups, respectively. The incidence of adverse events in three groups were 3.13%, 8.51% and 9.76% respectly, and has no significant difference. In addition, biochemical markers of bone metabolism including bone alkaline phosphatase (BAP), tartrate resistant acid phosphatase (TRAP) and dickkopf‐1 (DKK‐1), all improved in the three groups, although more significant in Group B than Group A, and more significant in the combination group than monotherapy groups. Conclusion: 99Tc‐MDP has good efficacy and safety in the treatment of active RA patients; the benefit was more remarkable when 99Tc‐MDP was combined with NSAIDs. 99Tc‐MDP may also have potential to improve bone metabolism. [ABSTRACT FROM AUTHOR]

Background: Delirium is a serious complication in patients in intensive care units. Previous surveys on delirium management in daily practice showed low adherence to published guidelines. Aim: To evaluate delirium management in nurses and physicians working in intensive care units in German-speaking countries and to identify related differences between nurses and physicians. Design: The study used an open online survey with multiple-choice responses. Methods: An invitation for participation was spread via journals and electronic resources using a snowball system. Apart from recording socio-demographical characteristics, the survey collected data on delirium assessment, delirium-related processes, non-pharmacological prevention and treatment and barriers for implementation. Differences between nurses and physicians were tested by Fisher's exact test with sequential Bonferroni correction. Results: The survey was conducted in autumn 2016, and 559 clinicians participated. More nurses than physicians reported screening for delirium. The majority of clinicians reported screening for delirium when this was suspected; more than 50% used validated instruments. Half of the clinicians had delirium-related structures implemented, such as two thirds reporting delirium-related processes. Most cited barriers were lack of time and missing knowledge about delirium and its assessment. With significant difference, physicians recommended more than nurses early removal of catheters and daily interprofessional goals for patients. Conclusion: In German-speaking countries, assessment of delirium needs further improvement, leading to accurate assessment. Delirium-related structures and processes appear to be implemented widely, with only a few differences between nurses and physicians. Relevance to clinical practice: Nurses and physicians in this survey reported similar perceptions and attitudes towards management of delirium. Both professions need more knowledge and inter-professional training on when and how to use validated assessment instruments. [ABSTRACT FROM AUTHOR]

Background and aims Prescription opioid overdose is a leading cause of injury-related morbidity and mortality in the United States. We aimed to identify characteristics associated with clinical severity in emergency department patients with prescription opioid overdose. Design This was a secondary data analysis of adult prescription opioid overdoses from a large prospective cohort of acute overdoses. We examined elements of a typical emergency department evaluation using a multivariable model to determine which characteristics were associated with clinical severity, specifically severe respiratory depression (SRD). Setting This study was conducted at two urban academic emergency departments in New York City, USA. Participants Adult patients who presented with acute prescription opioid overdose between 2009 and 2013 were included in the current study. We analyzed 307 patients (mean age = 44.7, 42% female, 2.0% mortality). Measurements Patient demographics, reported substances ingested, suspected intent for ingesting the substance, vital signs, laboratory data, treatments including antidotes and intubation and outcome of death were recorded by trained research assistants. Intent was categorized into four mutually exclusive categories: suicide, misuse, therapeutic error and undetermined. The primary outcome was SRD, defined as administration of either (a) naloxone or (b) endotracheal intubation (ETI). Findings A total of 109 patients suffered SRD with 90 patients receiving naloxone alone, nine ETI alone and 10 both naloxone and ETI. The most common opioids were oxycodone ( n = 124) and methadone ( n = 116). Mean age was higher in patients with SRD (51.1 versus 41.1, P < 0.001). Opioid misuse was associated with SRD in the multivariable analysis [odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.21-3.55]. The unadjusted relative risk of SRD was high for fentanyl (83.3% SRD) and lowest for codeine (3.6% SRD). Conclusion In emergency department patients in the United States with prescription opioid overdose, worse clinical severity was associated with opioid misuse, increased with age and was widely variable, depending on the specific opioid medication involved. [ABSTRACT FROM AUTHOR]

Problem The correlations between chronic endometritis and unexplained infertility are unexplored. Method of Study We performed a retrospective study on consecutive patients referred to our hysteroscopy service due to unexplained infertility. All women underwent endometrial sampling with histological and cultural examinations. If chronic endometritis was diagnosed, patients received antibiotic therapy, and chronic endometritis resolution was subsequently ascertained by histological examination. We aimed to estimate chronic endometritis prevalence and the effects of antibiotic therapy on spontaneous conception during the year following hysteroscopy. Results A total number of 95 women were included. Pooled prevalence of chronic endometritis was 56.8%. Antibiotic therapy resulted in chronic endometritis resolution in 82.3% of patients, while in 17.6% disease was persistent. Women with cured chronic endometritis showed higher pregnancy rate and live birth rate in comparison with both women with persistent disease and women without chronic endometritis diagnosis (pregnancy rate = 76.3% vs 20% vs 9.5%, P < .0001; live birth rate = 65.8% vs 6.6% vs 4.8%, P < .0001). Conclusion Chronic endometritis is highly prevalent in patients with unexplained infertility. Diagnosis and treatment of chronic endometritis improve spontaneous pregnancy rate and live birth rate in such patients. [ABSTRACT FROM AUTHOR]

Summary: Objective: Patients with temporal lobe epilepsy (TLE) show brain connectivity changes in association with cognitive impairment. Seizure frequency and lateralization are 2 important clinical factors that characterize epileptic seizures. In this study, we sought to examine an interactive effect of the 2 seizure factors on intratemporal effective connectivity based on resting‐state functional magnetic resonance imaging (rsfMRI) in patients with TLE. Methods: For rsfMRI data acquired from 48 TLE patients and 45 healthy controls, we applied stochastic dynamical causal modeling to infer effective connectivity between 3 medial temporal lobe (MTL) regions, including the hippocampus (Hipp), parahippocampal gyrus (PHG), and amygdala (Amyg), ipsilateral to the seizure focus. We searched for the effect of the 2 seizure factors, seizure frequency (good vs poor seizure control) and lateralization (left vs right TLE), on connection strengths and their relationship with the level of verbal memory and language impairment. Results: Impairment of verbal memory and language function was mainly affected by seizure lateralization, consistent with preferential involvement of the left MTL in verbal mnemonic processing. For the fully connected model, which was selected as the effective connectivity structure that best explained the observed rsfMRI time series, alterations in connection strengths were primarily influenced by seizure frequency; there was an increase in the strength of the Hipp to PHG connection in TLE patients with poor seizure control, whereas the strength of the Amyg to PHG connection increased in those with good seizure control. Furthermore, the association between connection strength alterations and cognitive impairment was interactively affected by both seizure frequency and lateralization. Significance: These findings suggest an interactive effect as well as an individual effect of seizure frequency and lateralization on neuroimaging features and cognitive function. This potential interaction needs to be evaluated in the consideration of multiple seizure factors. [ABSTRACT FROM AUTHOR]

Aim Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors. Methods Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale. Results Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count). Conclusion The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors. [ABSTRACT FROM AUTHOR]

Background A limitation to the expanded use of high-resolution pharyngeal manometry ( HRPM) in clinical practice is the lack of useful pharyngeal parameters that are easy to interpret, generalizable between patients, and do not require specialized software. In this study, we sought to test the relationship between the pharyngeal contractile integral ( PhCI) with videofluoroscopic abnormalities as assessed with the Modified Barium Swallow Impairment Profile©™. Methods Adult dysphagic patients were recruited to undergo simultaneous HRPM and videofluoroscopy during a standardized swallowing protocol. Key Results Thirty-six patients were included in the study. The mean PhCI was 247 mm Hg·cm·s (range 2-488 mm Hg·cm·s). The lower pharyngeal total ( PT) group (N=20; mean PT=3.9) had a mean PhCI of 299 mm Hg·cm·s, while the higher PT group (N=16; mean PT=12.7) had a mean PhCI score of 188 mm Hg·cm·s ( P=.01). There was also a significant negative correlation between normalized PhCI to PT scores ( r=−.47; P=.004). Patients with higher PhCIs exhibited less severe penetration-aspiration scores on thin liquids (1.44 vs 3.78; P=.03) and all consistencies combined (1.21 vs 1.99; P=.03). Conclusions & Inferences The PhCI is a useful indicator of the presence of pharyngeal swallowing impairment and is technically simple to calculate with currently available software programs. Advancement of software is necessary to refine the clinical value of this parameter. High-resolution pharyngeal manometry has the potential to be a valuable adjunct procedure for the evaluation and treatment of dysphagic individuals. [ABSTRACT FROM AUTHOR]

Plasma 1,3-β-D-glucan ( BDG) is indicated as a tool for early diagnosis of invasive fungal diseases ( IFD). However, data on its diagnostic value are scarce in children. Therefore, definition of BDG test performance in paediatrics is needed. BDG was evaluated in children admitted to 'Istituto Giannina Gaslini,' Genoa, Italy, who developed clinical conditions at risk for IFD. Results were analysed for sensitivity, specificity, predictive values, likelihood ratios, accuracy, informedness and probability of missing one case by a negative test. A total of 1577 BDG determinations were performed on 255 patients (49% males, median age 5.4 years). Overall 46 IFD were diagnosed, 72% proven/probable. The test performance was evaluated for 80 pg/mL, 120 pg/mL, 200 pg/mL, 350 pg/mL, 400 pg/mL cut offs. Sensitivity was always <0.80 and specificity > 0.90 only for cut offs ≥200 pg/mL. Negative predictive value was ≥0.90 for all the cut offs evaluated, while positive predictive value resulted barely 0.50 (8% IFD prevalence). Accuracy was never >0.90, and informedness was at best 0.50. The risk of missing one IFD by a negative result was < 10%. Analyses in haemato-oncological or newborn patients did not show major differences. Detection of serum BDG does not appear a valuable adjunctive diagnostic tool for IFD in paediatrics. [ABSTRACT FROM AUTHOR]

Objectives To assess long-term attachment and periodontitis-related tooth loss (PTL) in untreated periodontal disease over 40 years. Material and Methods Data originated from the natural history of periodontitis study in Sri Lankan tea labourers first examined in 1970. In 2010, 75 subjects (15.6%) of the original cohort were re-examined. Results PTL over 40 years varied between 0 and 28 teeth (mean 13.1). Four subjects presented with no PTL, while 12 were edentulous. Logistic regression revealed attachment loss as a statistically significant covariate for PTL ( p < .004). Markov chain analysis showed that smoking and calculus were associated with disease initiation and that calculus, plaque, and gingivitis were associated with loss of attachment and progression to advanced disease. Mean attachment loss <1.81 mm at the age of 30 yielded highest sensitivity and specificity (0.71) to allocate subjects into a cohort with a dentition of at least 20 teeth at 60 years of age. Conclusions These results highlight the importance of treating early periodontitis along with smoking cessation, in those under 30 years of age. They further show that calculus removal, plaque control, and the control of gingivitis are essential in preventing disease progression, further loss of attachment and ultimately tooth loss. [ABSTRACT FROM AUTHOR]

We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone ( VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation ( ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate ( ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival ( PFS) was 35·3 months and median overall survival ( OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months ( P < 0·0001), and median OS was 54·7 months versus not reached ( P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long-term follow-up, cytogenetic high risk is associated with markedly reduced PFS and OS post- ASCT. [ABSTRACT FROM AUTHOR]

Objectives: Rate control is an important component of the management of patients with atrial fibrillation (AF). Previous studies of emergency department (ED) rate control have been limited by relatively small sample sizes. We examined the use of beta-blockers (BBs) versus nondihydropyridine calcium channel blockers (CCBs) in ED patients from 24 sites and the associated hospital admission rates. Methods: In this preplanned substudy, we examined chart data on AF patients who visited one of 24 hospital EDs in Ontario, Canada, between April 2008 and March 2009. We describe the proportion of patients who received either a BB or a CCB, had a heart rate < 110 beats/min 2 hours later, and had any complications. We used hierarchical logistic regression modeling to determine the predictors of BB versus CCB use and to assess the between-hospital variation in use of BBs versus CCBs. Solely in patients who had no rhythm control attempts, we examined the difference in the probability of hospital admission after propensity score matching patients by medication class. Results: Of the 1,639 patients who received either a BB (n = 429) or a CCB (n = 1,210), 70.9% of the patients who received a BB had successful rate control versus 66.1% for a CCB. Complications were rare (2.4%), and the large majority were hypotension (2.0%). In adjusted analyses, predictors of receiving a BB (compared to a CCB) included already being on a BB, being sent in from a doctor’s office, or being seen at a teaching hospital. In contrast, patients with evidence of heart failure, prior use of a CCB, a higher presenting heart rate, or a successful pharmacologic cardioversion (vs. no attempt) or who were seen at the highest AF volume EDs were significantly less likely to receive a BB, compared to a CCB. Systematic between-hospital differences accounted for 8% of the variation in BB versus CCB use. Hospital characteristics accounted for the large majority of that variation: after accounting for patient characteristics the between-hospital variation decreased by a relative 2.8%. By further adjusting for hospital characteristics, it decreased by a relative 74.7%. Among propensity score–matched patients with no rhythm control attempts, more CCB patients were admitted (51.6%) compared to BB patients (40.0%; difference of 11.6%; 95% confidence interval = 7.9%–16.2%). Conclusions: In this study of 24 EDs, CCBs were used more frequently for rate control than BBs, and complications were rare and easily managed using both agents. Variation between hospitals in BB versus CCB use was predominantly due to hospital characteristics such as teaching status and AF volumes, rather than different case mix. Among patients who did not receive attempts at rhythm control, use of a BB for rate control was associated with a lower rate of hospitalization. [ABSTRACT FROM AUTHOR]

Objective: Gastroparesis is a debilitating condition that causes nausea, vomiting, and abdominal pain. Management includes analgesics and antiemetics, but symptoms are often refractory. Haloperidol has been utilized in the palliative care setting for similar symptoms. The study objective was to determine whether haloperidol as an adjunct to conventional therapy would improve symptoms in gastroparesis patients presenting to the emergency department (ED). Study Design and Methods: This was a randomized, double-blind, placebo-controlled trial of adult ED patients with acute exacerbation of previously diagnosed gastroparesis. The treatment group received 5 mg of haloperidol plus conventional therapy (determined by the treating physician). The control group received a placebo plus conventional therapy. The severity of each subject’s abdominal pain and nausea were assessed before intervention and every 15 minutes thereafter for 1 hour using a 10-point scale for pain and a 5-point scale for nausea. Primary outcomes were decreased pain and nausea 1 hour after treatment. Results: Of the 33 study patients, 15 were randomized to receive haloperidol. Before treatment, the mean intensity of pain was 8.5 in the haloperidol group and 8.28 in the placebo group; mean pretreatment nausea scores were 4.53 and 4.11, respectively. One hour after therapy, the mean pain and nausea scores in the haloperidol group were 3.13 and 1.83 compared to 7.17 and 3.39 in the placebo group. The reduction in mean pain intensity therapy was 5.37 in the haloperidol group (p ≤ 0.001) compared to 1.11 in the placebo group (p = 0.11). The reduction in mean nausea score was 2.70 in the haloperidol group (p ≤ 0.001) and 0.72 in the placebo group (p = 0.05). Therefore, the reductions in symptom scores were statistically significant in the haloperidol group but not in the placebo group. No adverse events were reported. Conclusions: Haloperidol as an adjunctive therapy is superior to placebo for acute gastroparesis symptoms. [ABSTRACT FROM AUTHOR]

A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%-10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis. [ABSTRACT FROM AUTHOR]

Background In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. Aim To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Methods Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. Results A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). Conclusion In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR. [ABSTRACT FROM AUTHOR]

The article presents a study which analyzed patients diagnosed with gray-zone lymphoma (GZL) at the University of Texas MD Anderson Cancer Center in Houston, Texas. Topics discussed include characteristics of patients with GZL, longer progression-free survival (PFS) found in patients with mediastinal GZL, and indication that dose-adjusted etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (DA-EPOCH-R) may improve outcome for patients with GZL.

Although high potent nucleos(t)ide analogues are strongly recommended as first-line therapy for chronic hepatitis B ( CHB) in China, some patients are still being treated with adefovir disoproxil ( ADV), especially those low-income patients whose health insurance could not reimburse the drug cost. Therefore, the management of patients who have failed ADV therapy or who sustained renal damage during ADV therapy remains an important clinical problem in China. This retrospective study aimed to compare the efficacy and safety of lamivudine ( LAM), telbivudine (LdT) or entecavir ( ETV) add-on strategies to optimize the treatment of patients with prior suboptimal response to ADV monotherapy. A total of 277 eligible patients were included in this study, and the baseline characteristics were similar among the LAM + ADV (n = 116), LdT + ADV (n = 72) and ETV + ADV (n = 89) groups. At week 96, both the proportion of undetectable HBV DNA (81.03% for LAM + ADV, 84.72% for LdT + ADV and 88.76% for ETV + ADV; P = .317) and ALT elevation (5.17% for LAM + ADV, 4.17% for LdT + ADV and 4.49% for ETV + ADV; P = 1.000) were similar among the three groups; also, a significant decline in liver stiffness was observed in each group from baseline to week 96. At week 96, the rate of HBeAg seroconversion was significantly higher in LdT + ADV than in LAM + ADV (26.39% vs 13.79%, P = .031) and ETV + ADV (26.39% vs 10.11%, P = .007). During the 96 weeks, no obvious renal injury was reported in any of the three groups, but an improvement in eGFR was found in LdT + ADV compared with LAM + ADV and ETV + ADV. In summary, all three combination strategies provide good control of virus replication, but the LdT + ADV combination therapy may yield better HBeAg seroconversion and eGFR improvement. [ABSTRACT FROM AUTHOR]

Background Differences in the gut microbiota and breath methane production have been observed in chronic constipation, but the relationship between colonic microbiota, transit, and breath tests remains unclear. Methods In 25 healthy and 25 constipated females we evaluated the sigmoid colonic mucosal and fecal microbiota using 16S rRNA gene sequencing, abundance of hydrogenogenic FeFe ( FeFe-hydA) and hydrogenotrophic (methyl coenzyme M reductase A [ mrcA] and dissimilatory sulfite reductase A [ dsrA]) genes with real-time qPCR assays, breath hydrogen and methane levels after oral lactulose, and colonic transit with scintigraphy. Key Results Breath hydrogen and methane were not correlated with constipation, slow colon transit, or with abundance of corresponding genes. After adjusting for colonic transit, the abundance of FeFehydA, dsrA, and mcrA were greater ( P<.005) in colonic mucosa, but not stool, of constipated patients. The abundance of the selected functional gene targets also correlated with that of selected taxa. The colonic mucosal abundance of FeFe-hydA, but not mcrA, correlated positively ( P<.05) with breath methane production, slow colonic transit, and overall microbiome composition. In the colonic mucosa and feces, the abundance of hydrogenogenic and hydrogenotrophic genes were positively correlated ( P<.05). Breath methane production was not associated with constipation or colonic transit. Conclusions & Inferences Corroborating our earlier findings with 16S rRNA genes, colonic mucosal but not fecal hydrogenogenic and hydrogenotrophic genes were more abundant in constipated vs. healthy subjects independent of colonic transit. Breath gases do not directly reflect the abundance of target genes contributing to their production. [ABSTRACT FROM AUTHOR]

Background and Purpose Oropharyngeal dysphagia ( OD) is a major complaint following stroke, associated with poor clinical outcome and high mortality rates. We aimed at characterizing the kinematics of swallow response associated with unsafe swallowing in chronic poststroke patients with OD. Patients and Methods Consecutive poststroke patients with a positive volume-viscosity swallow test for OD 3 months following stroke were studied by videofluoroscopy ( VFS). Demographical and clinical factors and kinematics of swallow response were compared between those poststroke patients with safe swallow (penetration-aspiration scale, PAS≤2) and those with unsafe swallow ( PAS≥3). Receiver operating characteristic ( ROC) curves were drawn for laryngeal vestibule closure ( LVC) time which predicts unsafe swallow. Results We studied 73 poststroke patients (76.7±9.3 years, 53.4% male) by VFS (60.4% with impaired safety, PAS=4.47±1.44, and 95.9% with impaired efficacy of swallow). Poststroke patients with unsafe swallow presented a poorer functional (Rankin 2.2±1.6 vs 1.2±1.0, P<.012) and nutritional status ( MNA-sf≤11, 34.2% vs 7.4%, P<.05) than poststroke patients with safe swallow. Poststroke patients with unsafe swallow presented a significant delay in LVC time (406.4±99.5 ms vs 318.9±80.4 ms; P<.05) and weaker tongue bolus propulsion forces (0.771±0.450 mJ vs 1.638±3.212 mJ; P=.043). LVC time ≥340 ms predicts unsafe swallow in chronic poststroke patients with a diagnostic accuracy of 0.78. Conclusions Impaired safety of swallow in chronic poststroke patients is caused by specific impairments in swallow response including delayed timing of airway protection mechanisms and weak tongue propulsion forces. Treatments aiming to restore swallowing function in poststroke patients with OD should be targeted to improve these critical biomechanical events. [ABSTRACT FROM AUTHOR]

Aim: Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital.Methods: Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health.Results: A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution.Conclusions: The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication. [ABSTRACT FROM AUTHOR]

Background The influence of surgery on olfaction in patients who suffer from chronic rhinosinusitis (CRS) is still not fully understood. Most particularly, the time course of the recovery is poorly studied. Methods The prospective study describes the results of the Sniffin' Sticks identification test in 41 subjects before (V1), 2 weeks after (V2), and 6 months after (V3) endonasal sinus surgery (ESS). Influencing factors (gender, revision surgery, nasal polyposis, and initial olfactory score) on the changes of the smell testing were evaluated. Results The whole cohort showed a significant improvement in Identification scores, from 8.63 to 10.24 after 2 weeks and to 10.68 after 6 months. Patients with nasal polyps revealed a similar increase in the identification test at V3 (+2.17 compared to +1.89 in those without polyps) but not at V2 (+1.30 compared to 2.00). The initial classification of olfaction was the only significant influencing factor. Patients who showed initially anosmic results improved (+4.87 at V2 and +4.73 at V3), as did patients in the hyposmic group (+0.58 resp. +1.42). Forty-four percent of the patients reached an improvement with regard to their diagnostic group. Conclusions This study of the evaluation of the sense of smell after ESS exhibits an improvement of olfaction already 2 weeks after surgery, which is stable for 6 months. CRSwNP and CRSsNP patients showed similar improvements of olfaction, although the recovery was slower in CRSwNP patients. Level of Evidence 2b. [ABSTRACT FROM AUTHOR]

Aims Varenicline was compared with transdermal nicotine (NRT) for smokers with current substance use disorders (SUD) for effects on 3-month smoking abstinence (primary outcome) and, secondarily, on 3- and 6 month abstinence while adjusting for medication adherence, and on additional smoking and substance use outcomes. Moderation by major depressive disorder history (MDD) and adherence were investigated. Design Double-blind double-placebo-controlled randomized design, stratifying by MDD, gender and nicotine dependence, with 3 and 6 months follow-up. Setting University offices in Rhode Island, USA. Participants Adult smokers ( n = 137), in SUD treatment, substance abstinent <12 months ( n = 77 varenicline, 60 NRT). Intervention and comparator Twelve weeks of varenicline (2 mg/day, after 1-week dose run-up) or NRT (21 mg/day decreasing to 7 mg/day). Measurements Primary: point-prevalence smoking abstinence (7-day, confirmed) at 3 months. Secondary: point-prevalence abstinence at 6 months, quantity and frequency of smoking and substance use at 3 and 6 months, and within-treatment abstinence, medication adherence and depressive symptoms. Smoking outcome analyses were repeated controlling for adherence and investigating adherence as a moderator. Findings Effects on 3-month abstinence were P < 0.065 without a covariate (Bayes factor 3.35, supporting the effect strongly) and differed significantly when controlling for baseline smoking [varenicline: 13%, NRT: 3%; odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.00, 23.13, P < 0.05]. The threefold difference at 6 months was not significant. Medication effect on abstinence across time was significant ( P < 0.05) covarying adherence and baseline smoking (OR = 6.40, 95% CI = 1.00, 40.93). Medication differences in 3-month abstinence occurred among participants with ≥ 77% adherence ( P < 0.02). No significant medication effects on heavy drinking, drug use or depressive symptoms were found. Conclusions Varenicline appears to improve the chances of achieving at least 3 months of smoking abstinence in smokers with substance use disorders trying to stop, compared with transdermal nicotine patches, the effect being independent of history of depressive disorder. [ABSTRACT FROM AUTHOR]

The management of Waldenström macroglobulinaemia ( WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide ( DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88 WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate ( ORR) was 87%. The median progression-free survival ( PFS) and time-to-next-therapy ( TTNT) were 32 (95% confidence interval [ CI]: 15-51) and 50 (95% CI: 35-60) months, respectively. In the previously untreated cohort ( n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23-not reached [ NR]) and NR (95% CI: 37- NR), respectively. Twenty-five (86%) of 29 genotyped patients harbored MYD88L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well-tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients' MYD88 status. [ABSTRACT FROM AUTHOR]

Around half of the global adult HIV-positive population are women, yet historically women have been under-represented in clinical studies of antiretroviral therapy (ART) and there has been minimal exploration of gender-specific factors related to the response to and appropriateness of treatment choices in women living with HIV (WLWH). There are several key issues pertaining to the cascade of HIV care that make it important to differentiate WLWH from men living with HIV. Factors that are gender specific may impact on the status of WLWH, affecting access to diagnosis and treatment, optimal clinical management, ART outcomes, retention in care, and the overall long-term wellbeing of WLWH. In this review, we discuss the results of recently reported women-only clinical trials and highlight the key unmet needs of WLWH as they pertain to the cascade of HIV care across World Health Organization European Region countries. As significant knowledge gaps remain, the review identifies key areas where further research is required, in order to support improved management of WLWH and guide informed clinical decision-making, including addressing psychosocial factors as part of comprehensive care. [ABSTRACT FROM AUTHOR]

Therapy resistance of approximately one-third of patients with Gilles de la Tourette syndrome ( GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning-induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non-invasive and invasive brain stimulation techniques as a novel platform for non-pharmacological neuromodulation of GTS symptoms. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Glycaemic control is recognized as one of the important aspects in managing critically ill patients. Both hyperglycaemia and hypoglycaemia independently increase the risk of patient mortality. Hence, the identification of optimal glycaemic control is of paramount importance in the management of critically ill patients. Aims and objectives The aim of this literature review is to examine the current status of glycaemic control in critically ill adult patients. This literature review will focus on randomized controlled trials comparing intensive insulin therapy to conventional insulin therapy, with an objective to identify optimal blood glucose level targets for critically ill adult patients. Design and methods A literature review was conducted to identify large randomized controlled trials for the optimal targeted blood glucose level for critically ill adult patients published since 2000. A total of eight studies fulfilled the selection criteria of this review. Results With current human and technology resources, the results of the studies support commencing glycaemic control once the blood glucose level of critically ill patients reaches 10 mmol/L and maintaining this level between 8 mmol/L and 10 mmol/L. Conclusion This literature review provides a recommendation for targeting the optimal blood glucose level for critically ill patients within moderate blood glucose level target range (8-10 mmol/L). The need for uniformed glucometrics for unbiased reporting and further research for optimal blood glucose target is required, especially in light of new technological advancements in closed-loop insulin delivery and monitoring devices. Relevance to clinical practice This literature review has revealed a need to call for consensus in the measurement and reporting of glycaemic control using standardized glucometrics. [ABSTRACT FROM AUTHOR]

Background Porokeratosis ptychotropica ( PP) is a rare variant of porokeratosis with a special predisposition to affect body folds, particularly the intergluteal cleft. This disease is resistant to most topical and systemic treatments, as shown in the review of the literature we provide here. Itching and discomfort are often a difficult problem to solve. Patients and Methods Two patients with PP that had not responded to multiple topical treatments were treated with photodynamic therapy ( PDT). Changes in plaque size, thickness and symptoms were assessed after treatment. Results Pruritus disappearance was observed in both patients after treatment with PDT. Partial clearance of the plaques was observed in one case. In the other case, a moderate clearance of hyperkeratosis was observed, although the size of the lesions persisted unchanged. Conclusions PDT seems to be a good therapeutic alternative in the treatment of PP, as it can provide symptomatic relief and clinical improvement of the lesions. However, it does not appear to be a curative treatment. Moreover, long-term response is still unknown. [ABSTRACT FROM AUTHOR]

Background We have previously reported a non-invasive, semi-automated technique to assess motility of the wall of the ascending colon ( AC) using Magnetic Resonance Imaging. This study investigated the feasibility of using a tagged MRI technique to visualize and assess the degree of flow within the human ascending colon in healthy subjects and those suffering from constipation. Methods An open-labeled study of 11 subjects with constipation and 11 subjects without bowel disorders was performed. MRI scans were acquired fasted, then 60 and 120 minutes after ingestion of a 500 mL macrogol preparation. The amount of free fluid in the small and large bowel was assessed using a heavily T2-weighted MRI sequence. The internal movement of the contents of the AC was visualized using a cine tagged MRI sequence and assessed by a novel analysis technique. Comparisons were made between fasting and postprandial scans within individuals, and between the constipation and control groups. Key Results Macrogol significantly increased the mobile, MR visible water content of the ascending colon at 60 minutes postingestion compared to fasted data (controls P=.001, constipated group P=.0039). The contents of the AC showed increased motion in healthy subjects but not in the constipated group with significant differences between groups at 60 minutes ( P<.002) and 120 minutes ( P<.003). Conclusions and inferences This study successfully demonstrated the use of a novel MRI tagging technique to visualize and assess the motion of ascending colon contents following a 500 mL macrogol challenge. Significant differences were demonstrated between healthy and constipated subjects. [ABSTRACT FROM AUTHOR]