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Background: Rib fractures are common sequelae after blunt chest wall trauma. They can occur in isolation or association with life-threatening injuries to the head, thorax, and abdomen and may be complicated by hemothorax, pneumothorax, or lung contusions. Contiguous rib fractures can result in flail chest, which is associated with increased morbidity and mortality. This study aims to compare the risk factors, treatment modalities, and outcomes between patients with flail chest and nonflail chest postblunt trauma. Patients and Methods: Data were retrospectively collected from all patients admitted with rib fractures from January 2016 to December 2016 to the Department of General Surgery, Khoo Teck Puat Hospital, Singapore. The outcomes identified were mortality, pain scores on injury day 1, 3, 5, and 7, injury severity score, duration of mechanical ventilation, worst partial pressure arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio, length of intensive care unit (ICU) stay, and pulmonary complications. Results: Motor vehicle accident was the most common cause of rib fractures (63.1%, n = 123). Patients with flail chest had more associated pneumothorax (53.8% vs. 35.2%) and lung contusions (53.8% vs. 30.2%) compared to those without flail chest and underwent more investigations such as inpatient-computed tomography scans (76.9% vs. 59.3%), interventions such as chest tube insertion (61.5% vs. 19.8%), and ICU admission (46.1 vs. 13.7%). Patients also had higher pain scores, used more analgesic modalities, and had increased inpatient mortality (30.8% vs. 4.4%). Conclusion: Flail chest is associated with higher morbidity and mortality. Proactive management from a multidisciplinary team such as identification of high-risk patients in particular patients with flail chest, early admission to critical care, and protocols including multimodal pain management, respiratory support, and rehabilitation should be instituted. [ABSTRACT FROM AUTHOR]

Purpose Prostate specific antigen based screening for prostate cancer has had a significant impact on the epidemiology of the disease. Its use has been associated with a significant decrease in prostate cancer mortality but has also resulted in the over diagnosis and overtreatment of indolent prostate cancer, exposing many men to the harms of treatment without benefit. The USPSTF (U.S. Preventive Services Task Force) in 2008 issued a recommendation against screening men older than 75 years, and in 2012 against routine screening for all men, indicating that in its interpretation the harms of screening outweigh the benefits. We review changes in the use of prostate specific antigen testing, performance of prostate biopsy, incidence of prostate cancer and stage of disease at presentation since 2012. Materials and Methods An English language literature search was performed for terms that included “prostate specific antigen,” “screening” and “United States Preventive Services Task Force” in various combinations. A total of 26 original studies had been published on the effects of the USPSTF recommendations on prostate specific antigen based screening or prostate cancer incidence in the United States as of December 1, 2016. Results Review of the literature from 2012 through the end of 2016 indicates that there has been a decrease in prostate specific antigen testing and prostate biopsy. As a result, there has been a decline in the incidence of localized prostate cancer, including low, intermediate and high risk disease. The data regarding stage at presentation have yet to mature but there are some early signs of a shift toward higher burden of disease at presentation. Conclusions These findings raise concern about a reversal of the observed improvement in prostate cancer specific mortality during preceding decades. Alternative screening strategies would 1) incorporate patient preferences by allowing shared decision-making, 2) preserve the survival benefits associated with screening, 3) improve the specificity of screening to reduce unnecessary biopsies and detection of low risk disease, and 4) promote the use of active surveillance for low risk cancers if they are detected. [ABSTRACT FROM AUTHOR]

Glaucoma is a leading cause of irreversible blindness worldwide. The reduction of intraocular pressure has been well established as an effective treatment to prevent both the development and the progression of all forms of glaucoma. Bimatoprost 0.03% ophthalmic solution, introduced in 2001, is a synthetic prostamide with the unique mechanism of improving both uveoscleral and trabecular outflow. Comparative studies with other pharmacotherapies have shown favorable results for bimatoprost as a potent ocular hypotensive agent that is generally well tolerated. Common side effects include conjunctival hyperemia, eyelash growth, iris pigmentation and periorbital changes. Hyperemia rates were reduced following the introduction of bimatoprost 0.01%. Bimatoprost should be used with caution in those with higher risk of developing ocular inflammation and macular edema. However, the perceived risk of bimatoprost in these patient populations is likely greater than the actual risk observed in practice. Bimatoprost is currently in the center of several clinical trials including its use for dermatologic applications and sustained-release therapies for the treatment of ocular hypertension and glaucoma. [ABSTRACT FROM AUTHOR]

Background: Gene-expression classifiers (GEC) and genetic mutation panels (GMP) have been shown to improve preoperative diagnostic evaluations of indeterminate thyroid nodules. Despite the improvement, uncertainty regarding the proper management exists. Patient preferences may better inform the management of these indeterminate thyroid nodules. Methods: Hypothetical scenarios were administered to two groups of patients: those with previous FNA-confirmed indeterminate thyroid nodules (Group A, n = 50) and those presenting to a general otolaryngology clinic for other reasons (Group B, n = 50). We evaluated patient preferences for surgery, observation and the use of molecular tests while varying the risk of malignancy, cost and diagnostic properties of the tests. Results: The mean threshold for choosing surgery over observation was a 38.6% risk of malignancy on FNA. When offered either GEC, GMP or both (with their inherent imperfect diagnostic properties) in addition to the indeterminate FNA, 85.0% of respondents picked at least one of the molecular tests over either observation or surgery if the test(s) were free of charge. However, only 51.7% of respondents chose at least one of the tests when asked to pay the current cost of the test(s) ( p < 0.001). On multivariable analysis, sex, the presence of an indeterminate FNA diagnosis and income level significantly predicted the desire to proceed with a molecular test above standard management. Conclusion: Patient preferences for thyroid nodule management are dependent on the risk of malignancy, prognosis of cancer and costs. Patients prefer molecular tests over standard management with indeterminate thyroid nodules, but the costs of the test(s) reduce the desire. [ABSTRACT FROM AUTHOR]

Background: The first step in manufacturing chimeric antigen receptor (CAR) T cells is to collect autologous CD3+ lymphocytes by apheresis. Patients, however, often have leukopenia or have other disease-related complications. We evaluated the feasibility of collecting adequate numbers of CD3+ cells, risk factors for inadequate collections, and the rate of adverse events.Study Design and Methods: Apheresis lymphocyte collections from patients participating in three CAR T-cell clinical trials were reviewed. Collections were performed on the COBE Spectra by experienced nurses, with the goal of obtaining a minimum of 0.6 × 109 and a target of 2 × 109 CD3+ cells. Preapheresis peripheral blood counts, apheresis parameters, and product cell counts were analyzed.Results: Of the 71 collections, 69 (97%) achieved the minimum and 55 (77%) achieved the target. Before apheresis, the 16 patients with yields below the target had significantly lower proportions and absolute numbers of circulating lymphocytes and CD3+ lymphocytes and higher proportions of circulating blasts and NK cells than those who achieved the target (470 × 106 lymphocytes/L vs. 1340 × 106 lymphocytes/L, p = 0.008; 349 × 106 CD3+ cells/L vs. 914 × 106 CD3+ cells/L, p = 0.001; 17.6% blasts vs. 4.55% blasts, p = 0.029). Enrichment of blasts in the product compared to the peripheral blood occurred in four patients, including the two patients whose collections did not yield the minimum number of CD3+ cells. Apheresis complications occurred in 11 patients (15%) and, with one exception, were easily managed in the apheresis clinic.Conclusions: In most patients undergoing CAR T-cell therapy, leukapheresis is well tolerated, and adequate numbers of CD3+ lymphocytes are collected. [ABSTRACT FROM AUTHOR]

Objective The goal of this study was to analyze whether tympanic plexus neurectomy is a successful surgical option in patients with intractable otalgia. Study Design A retrospective single institution study from the experience of two surgeons was conducted. Methods Records of adult patients with intractable unilateral otalgia of likely glossopharyngeal origin were reviewed, with institutional review board approval. Patients who responded to a tympanic plexus block were considered for tympanic neurectomy. Twelve patients (13 ears) underwent the procedure. Surgical outcomes and the presence of persistent otalgia were evaluated. Results Persistent otalgia was present for 16.7 months ± 8.6 standard-error-of-the-mean months prior to an intervention. Narcotic medication was used in 41.7% of patients prior to surgery. Patients received tympanic plexus blocks (median: 1, range 1-3) prior to tympanic neurectomy to evaluate candidacy for surgery. Intractable otalgia resolved in six of 13 ears (46.2%) after one surgery, with an average follow-up of 25.5 months. A significant reduction in pain occurred in two of 13 ears (15.4%) after an initial surgery. One patient received no benefit from the initial procedure. Revision surgery occurred in four ears, resulting in pain relief in three of four cases. All together, nine of 13 ears received complete resolution of pain, and an additional two of 13 ears received partial benefit using our algorithm for treatment of intractable otalgia of tympanic plexus origin. Conclusion Intractable otalgia treated with tympanic neurectomy is a viable treatment option in cases of failed medical management. These findings provide important information that will aid clinicians in counseling chronic otalgia patients. Level of Evidence NA. [ABSTRACT FROM AUTHOR]

Objective: To characterize the safety and efficacy of the 180-W XPS-Greenlight laser in patients on systemic anticoagulation.Materials and Methods: A retrospective analysis of 384 patients who underwent photoselective vaporization of the prostate with the 180-W XPS-laser between 2010 and 2013 at two centers in the United States and Switzerland was performed. The primary outcome was the intraoperative and postoperative complication rates for those on anticoagulation undergoing photoselective vaporization of the prostate. The secondary outcome was International Prostate Symptom Scores, postvoid residual, maximum flow rate, and prostate-specific antigen levels.Results: Of 384 patients, aspirin, clopidogrel, and warfarin were used in 146 (38%), 34 (8.9%), and 57 (14.8%) patients, respectively. Single-drug, two-drug, and three-drug combinations were used in 142 (35.5%), 37 (9.3%), and 7 (1.7%) of the cases. Median lasing time (39 min vs 36 min; P = .99) and number of fibers used (1.0 vs 1.0; P = .63) were comparable between patients on vs off systemic anticoagulation. Postoperatively, urinary symptoms (International Prostate Symptom Score, quality of life) and objective voiding parameters (maximum flow rate, postvoid residual) improved in both groups of patients. During a maximum follow-up of 2 years, patients on vs off systemic anticoagulation did not show any significant differences in the rate of postoperative urinary tract infection (3.8% vs 5.1%; P = .71), retention (5.1% vs 5.9%; P = .71), urethral stricture (1.5% vs none, P = .05), and reoperation (2.2% vs 1.5%; P = .49). The primary limitation is the retrospective nature of the study.Conclusion: Photovaporization of the prostate with the 180-W XPS-laser is a safe and effective minimal-invasive treatment option for patients on systemic anticoagulation. [ABSTRACT FROM AUTHOR]

Objective: The aim was to assess gabapentin enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS).Methods: Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied.Results: The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n = 204; GEn 600 mg, n = 114; GEn 1200 mg, n = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p < 0.01). The mood analysis MITT population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). GEn 600 mg significantly improved POMS vigor-activity versus placebo (week 12; p < 0.05); other POMS criteria were not significantly affected. GEn 1200 mg significantly improved POMS scores for total mood disturbance, depression-dejection, fatigue-inertia, vigor-activity, and confusion-bewilderment versus placebo at week 12 (p < 0.05); tension-anxiety and anger-hostility were not significantly affected. Both GEn doses significantly improved IRLS item 9 and item 10 versus placebo at week 12 (p < 0.05). The most frequent treatment-emergent adverse events with GEn were somnolence and dizziness.Conclusions: GEn (600 mg and 1200 mg) once daily significantly improved QOL in adults with moderate-to-severe primary RLS at all time points examined. While the only POMS item significantly improved by GEn 600 mg versus placebo at week 12 was vigor-activity, GEn 1200 mg significantly improved total mood disturbance and several other POMS items versus placebo at week 12. Both QOL and mood improvements were numerically greater with GEn 1200 mg versus 600 mg.Trial Registrations: Clinicaltrials.gov identifiers NCT00298623, NCT00365352, NCT01332305. [ABSTRACT FROM AUTHOR]

Aim: Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS).Methods: We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression - Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed.Results: A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, -12.3; GEn 600 mg, -16.3; GEn 1200 mg, -18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21-24%; placebo, 3%) and dizziness (GEn, 14-19%; placebo, 3%).Conclusions: GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of transdermal scopolamine for treatment of postoperative nausea and vomiting (PONV) after robotic-assisted gynecologic surgery. Design: Prospective, randomized, double-blinded, placebo-controlled clinical trial. Method: Overall, 47 patients underwent robotic-assisted gynecologic surgery at two tertiary care hospitals, and they were randomized to receive transdermal scopolamine or placebo preoperatively. They then completed a series of questionnaires utilizing a visual analogue scale to rate their nausea and vomiting. Main outcomes were severity of nausea and vomiting till 72 hours postoperatively. Secondary outcomes were antiemetic use, time to discharge, effect on patient well-being of PONV, and patient overall well-being. Results: There was a benefit to the number of rescue antiemetics administered in the immediate postoperative period (0.30 vs. 0.70, p=0.026), but no significant reduction in incidence or severity of PONV, no overall decrease in amount of antiemetics used, no change in length of hospital stay, and no impact on patient well-being with use of scopolamine. Conclusion: Rates of PONV in this robotic population of patients using multi-modality therapy are less than 40%. Further studies are needed to investigate the use of transdermal scopolamine for prevention of PONV after robotic-assisted gynecologic surgery, as the only significant benefit of its use compared with placebo was a reduction in the number of rescue antiemetics administered in the first 6 hours postoperatively. (J GYNECOL SURG 31:266) [ABSTRACT FROM AUTHOR]

Objective Few studies have examined operative times for cochlear implantation (CI) using multivariable linear regression analyses to identify predictors of case length. Herein, we assess whether trainee participation, among other factors, influences operating room (OR) times. Methods We retrospectively reviewed total OR and procedural times for isolated unilateral implants over a 5-year period (2009–2013) in children and adults. Total operating and procedural times were compared. Multivariable linear regression analyses were used to identify predictors of procedural time. Results We identified a total of 455 unilateral CI procedures (n = 35 pediatric, n = 420 adult). Mean total OR time was 193.6 minutes (SD = 58.9 minutes) and mean procedural time was 147.1 minutes (SD = 56.2). The presence of trainees was associated with a significant difference in procedure time: 149.9 minutes (SD = 54.9) with trainees versus 136.6 minutes (SD = 59.9) without trainees, P = 0.0375. Trainee involvement did not significantly increase total OR time: 196.3 minutes (SD = 56.9) with trainees versus 183.8 minutes (SD = 65.0) without trainees, P = 0.0653. Surgeon identity was also associated with differences in procedural time (P < 0.001). Patient age, gender, American Society of Anesthesiologists classification, and pediatric designation had no significant impact on length of case. Conclusions Major predictors of longer procedural OR times for CI are surgeon identity and trainee participation. Few published data exist on length of CI in an academic setting using multivariable linear regression analyses. Our data may be instructive for comparative analyses and have implications for operative planning and surgical education. [ABSTRACT FROM AUTHOR]

The article offers information on the complications of systemic therapy in gut infections and diarrhea patients. Topics discussed include use of anti-diarrheas early and aggressively for proper management of diarrhea in patients with cancer, reducing the morbidity associated with treatment route, and production of irinotecan metabolites within the gastrointestinal tract.

Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1 BB signaling domain to CD28.CD3ζ constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL. (Blood. 2013;121 (7):1165-1174) [ABSTRACT FROM AUTHOR]

BACKGROUND: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS: Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article discusses a randomized trial that compares the effectiveness of oral corticosteriods compared with intratympanic steroid to treat sudden sensorineural hearing loss. The study revealed that the hearing level two months following treatment demonstrated that intratympanic treatment was not inferior to oral prednisone treatment. Pure tone average (PTA) improved by 30.7 decibels (dB) in the oral prednisone group compared with a 28.7-dB improvement in the intratympanic treatment group. At two months, average PTA was 56.0 dB for the oral steroid treatment group and 57.6 dB for the intratympanic treatment group.

Abstract: The use of recombinant adeno-associated viral (rAAV) vectors as a means of gene delivery to the central nervous system has emerged as a potentially viable method for the treatment of several types of degenerative brain diseases. However, a limitation of typical intracranial injections into the adult brain parenchyma is the relatively restricted distribution of the delivered gene to large brain regions such as the cortex, presumably due to confined dispersion of the injected particles. Optimizing the administration techniques to maximize gene distribution and gene expression is an important step in developing gene therapy studies. Here, we have found additive increases in distribution when 3 methods to increase brain distribution of rAAV were combined. The convection enhanced delivery (CED) method with the step-design cannula was used to deliver rAAV vector serotypes 5, 8 and 9 encoding GFP into the hippocampus of the mouse brain. While the CED method improved distribution of all 3 serotypes, the combination of rAAV9 and CED was particularly effective. Systemic mannitol administration, which reduces intracranial pressure, also further expanded distribution of GFP expression, in particular, increased expression on the contralateral hippocampi. These data suggest that combining advanced injection techniques with newer rAAV serotypes greatly improves viral vector distribution, which could have significant benefits for implementation of gene therapy strategies. [ABSTRACT FROM AUTHOR]

Abstract: The extracellular signal-regulated kinase 1/2 (ERK) pathway, part of the mitogen-activated protein kinase (MAPK) family, is well-known for its role in cell differentiation and proliferation. In the context of osteoclastogenesis, macrophage colony stimulating factor (M-CSF) is an upstream activator of ERK signals for the survival of osteoclast precursors prior to their differentiation into multinucleated osteoclasts. In this study, we demonstrate by using both in vivo and in vitro models that the ERK signaling pathway involves an inflammatory response of various cells mediating osteolysis. Osteoblasts exhibit innate immune response by expressing M-CSF in response to lipopolysaccharide (LPS). LPS induced M-CSF expression is mediated by ERK. The inhibition of ERK signaling attenuated the inflammatory response to LPS both in vivo and in vitro. Thus, the ERK pathway may be a potentially important therapeutic target in the treatment of inflammatory osteolysis. [Copyright &y& Elsevier]

Lung cancer has traditionally been viewed as being difficult to treat and generally associated with a poor outcome. With new advances in technology and medicine in general, the public has come to expect a better prognosis from lung cancer. Once a patient has been referred with suspected lung cancer, it is important to confirm the diagnosis and to stage the cancer; in this way, one can ascertain whether or not the cancer is potentially operable. By providing definitive surgery, the aim is to cure the patient of cancer. The role of staging extends beyond that of merely directing appropriate therapy or determining the patient pathway (be it supportive, palliative or curative); it also has prognostic implications including the likelihood of survival from lung cancer. [ABSTRACT FROM AUTHOR]

Presents the results of a qualitative systematic review of studies assessing best practices for handling potassium products in hospitals that will ensure medication and patient safety. Recommendations for drug storage, preparation, packaging, prescribing, and administration; Suggestion that there should be a unique industry standard for labelling and packaging of products containing concentrated potassium.

Presents a clinical review on asthma management. Chronic asthma with non-pharmacological management; Pharmacological management; Acute asthma treatments; Future treatments;Need for further studies on what to do when the asthma becomes less well controlled; Lack of evidence that dietary manipulation or the Buteyko technique offer any benefit. INSETS: Summary points;Key components of a written asthma action plan;Medical and psyhosocial features associated with a fatal or near.

There are no data comparing the relative efficacy of hydrofluoroalkane (HFA) formulations of ciclesonide (CIC) and fluticasone propionate (FP) on airway hyper-responsiveness, in mild-to-moderate persistent asthma. We therefore elected to evaluate the comparative efficacy of HFA pressurized metered-dose inhaler formulations of CIC and FP, assessing methacholine challenge, in addition to exhaled nitric oxide, lung function, diary cards and quality of life. Nineteen mild-to-moderate asthmatic patients completed the study per protocol in randomized, double-blind, double-dummy, crossover fashion. Patients were required to stop their usual inhaled corticosteroid therapy for the duration of the study. Pa-tients were commenced instead on salmeterol (SM) 50 µg one puff twice daily + montelukast (ML) 10 mg once daily for 2-week washout periods prior to each randomized treatment, in order to prevent dropouts. Patients received 4 weeks of either CIC 200 µg two puffs once daily (08.00 h) + CIC-placebo (PL) two puffs once daily (20.00 h) + FP-PL two puffs twice daily (08.00 h and 20.00 h), or FP 125 µg two puffs twice daily (08.00 h and 20.00 h) + CIC-PL two puffs twice daily (08.00 h and 20.00 h). SM + ML were withheld for 72 h prior to post-washout visits and CIC or FP was withheld for 24 h prior to study visits. There was no significant difference between CIC vs. FP for the primary outcome of methacholine P C20 as doubling dilution (dd) shift from respective baseline; mean difference: 0.4 dd (95% CI −0.4, 1.2). Moreover, there was no difference between treatments for the sequence of CIC first vs FP second; mean difference: 0.2 dd (95% CI −1.3, 1.7) or FP first vs CIC second; mean difference: 0.9 dd (95% CI −0.1, 1.8). There were also no differences for other secondary outcomes between treatments, either respective or irrespective of sequence, as change from baseline. There were no differences between 4 weeks of CIC 400 µg once daily and FP 250 µg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Longer-term studies are indicated to evaluate their relative efficacy on asthma exacerbations. [ABSTRACT FROM AUTHOR]

Axonal damage is a key pathology in many injuries of the central nervous system (CNS), such as spinal cord injury, traumatic brain injury and stroke, as well as in multiple sclerosis. An attractive drug discovery strategy to treat such conditions is to search for agents that promote CNS axonal regeneration. Historically, limited knowledge concerning the basis of poor CNS regeneration has precluded a rational drug discovery approach for promoting axonal regeneration. The recent identification of the Nogo receptor, which interacts with inhibitory myelin protein, established the crucial role of this molecular pathway in mediating the inhibitory effects of CNS myelin. This provides an unprecedented opportunity to manipulate adult CNS axonal regeneration. The development of therapeutics targeting the Nogo receptor has the potential to promote functional recovery and reverse the devastating consequences of CNS injuries. [ABSTRACT FROM AUTHOR]

Aim Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C[sub 4] synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme. Methods We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed m our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils. Results For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) (n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63-1.81) and 1.02 (95%CI 0.70-1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes. Conclusion Polymorphisms of leukotriene C[sub 4] synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists m mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide. [ABSTRACT FROM AUTHOR]

Objective. Current guidelines advocate adding a long acting β2-agonist (LABA) to an inhaled corticosteroid as an alternative to increasing the dose of the latter. Since it is unclear how this translates into effects on surrogate inflammatory markers, we evaluated the anti-inflammatory activity of fluticasone plus salmeterol in combination versus twice the dose of fluticasone alone. Methods. Fifteen mild-to-moderate asthmatics (mean FEV1 80% predicted) uncontrolled on inhaled corticosteroids (mean dose 470 μg) were randomised in a single-blind crossover fashion to receive 2 weeks each of fluticasone 250 µg plus salmeterol 50 µg in combination (FP+SM), 1 puff b.i.d., and fluticasone 500 µg (FP), 1 puff b.i.d. Prior to each randomised treatment, there was a 2-week run-in and washout period during which patients used their usual inhaled corticosteroid therapy. Measurements were made before and after randomised treatment periods. The primary outcome was airway hyper-responsiveness to adenosine monophosphate (AMP PC20), while secondary endpoints were exhaled tidal nitric oxide (NO), forced expiratory volume in 1 second (FEV1) and forced mid-expiratory flow (FEF25–75). Results. For AMP PC20, FP alone but not FP+SM conferred a significant (P<0.05) improvement amounting to 3.27 (95% CI 1.46–7.32) and 1.44 (95% CI 0.64–3.23) geometric mean fold shifts, respectively, from baseline, while the difference between treatments was significantly (P<0.05) greater with FP alone: a 2.26-fold (95% CI 1.01–5.07) difference. Both FP alone and FP+SM conferred significant (P<0.05) falls in NO from baseline: 2.33 (95% CI 1.71–3.19) and 1.49 (95% CI 1.09–2.03) geometric mean fold changes, respectively, while between treatments the reduction was significantly (P<0.05) greater with FP alone: a 1.57-fold (95% CI 1.15–2.14) difference. Neither treatment significantly improved FEV1 or FEF25–75. Conclusion. Double the dose of FP alone relative to FP+SM conferred superior effects on surrogate inflammatory markers but not on lung function. Long-term studies are required to evaluate whether these improvements on surrogate inflammatory markers translate into commensurate reductions in airway remodelling and exacerbations. [ABSTRACT FROM AUTHOR]

The article focuses on Esophagectomy as the method of treatment of high-grade dysplasia in Barrett's esophagus. The controversy regarding the treatment of high-grade dysplasia arises because of the unawareness about its natural history. The risks and benefits of the Esophagectomy should be considered against the results of therapy with alternate ways of treatment.

The article looks at oral treatments of chronic obstructive pulmonary disease. The article discusses the clinical use of theophylline, its adverse effects, including hypokalemia and tachycardia, oral corticosteroids, corticosteroid induced osteoporosis, oxygen therapy, symptomatic peripheral oedema, and low dose diuretics.

Presents a letter to the editor about the butterbur therapy for the treatment of allergic rhinitis.

Background: Abnormal tau hyperphosphorylation and its accumulation into intra-neuronal neurofibrillary tangles are linked to neurodegeneration in Alzheimer's disease and similar tauopathies. One strategy to reduce accumulation is through immunization, but the most immunogenic tau epitopes have so far remained unknown. To fill this gap, we immunized mice with recombinant tau to build a map of the most immunogenic tau epitopes.Methods: Non-transgenic and rTg4510 tau transgenic mice aged 5 months were immunized with either human wild-type tau (Wt, 4R0N) or P301L tau (4R0N). Each protein was formulated in Quil A adjuvant. Sera and splenocytes of vaccinated mice were collected to assess the humoral and cellular immune responses to tau. We employed a peptide array assay to identify the most effective epitopes. Brain histology was utilized to measure the effects of vaccination on tau pathology and inflammation.Results: Humoral immune responses following immunization demonstrated robust antibody titers (up to 1:80,000 endpoint titers) to each tau species in both mice models. The number of IFN-γ producing T cells and their proliferation were also increased in splenocytes from immunized mice, indicating an increased cellular immune response, and tau levels and neuroinflammation were both reduced. We identified five immunogenic motifs within either the N-terminal (9-15 and 21-27 amino acids), proline rich (168-174 and 220-228 amino acids), or the C-terminal regions (427-438 amino acids) of the wild-type and P301L tau protein sequence.Conclusions: Our study identifies five previously unknown immunogenic motifs of wild-type and mutated (P301L) tau protein. Immunization with both proteins resulted in reduced tau pathology and neuroinflammation in a tau transgenic model, supporting the efficacy of tau immunotherapy in tauopathy. [ABSTRACT FROM AUTHOR]

Acute heart failure syndromes (AHFS), with a high post-discharge mortality and rehospitalization rate, represent a significant public health burden. The treatment of patients hospitalized with AHFS often includes the use of vasoactive medications such as inotropes and vasodilators. Although such agents are frequently used, their safety and efficacy remain controversial. A significant number of patients with heart failure have underlying coronary artery disease and may be at greater risk from hemodynamic alterations that can diminish coronary perfusion. In AHFS, the relationship among vasoactive medications, coronary perfusion, and potential myocardial injury needs further investigation. Newer techniques now available to evaluate coronary perfusion should provide guidance for the evaluation of existing and future vasoactive therapies for AHFS. [Copyright &y& Elsevier]

The article discusses the neurotoxicity due to the anti-CD19 chimeric antigen receptor (CAR) T cells, highlighting the effects of inflammatory cytokines and the permeability of blood-brain barrier. It examines the central nervous system, use of tocilizuma for the treatment, and the evaluation of the cerebrospinal fluid.

Background aims. Autologous chimeric antigen receptor (CAR) T-cell therapies have shown promising clinical outcomes, but T-cell yields have been variable. CD19- and GD2-CAR T-cell manufacturing records were reviewed to identify sources of variability. Methods CD19-CAR T cells were used to treat 43 patients with acute lymphocytic leukemia or lymphoma and GD2-CAR T cells to treat eight patients with osteosarcoma and three with neuroblastoma. Both types of CAR T cells were manufactured using autologous peripheral blood mononuclear cells (PBMC) concentrates and anti-CD3/CD28 beads for T-cell enrichment and simulation. Results A comparison of the first 6 GD2- and the first 22 CD19-CAR T-cell products manufactured revealed that GD2-CAR T-cell products contained fewer transduced cells than CD19-CAR T-cell products (147 ± 102 × 106 vs 1502 ± 1066 × 106; P = 0.0059), and their PBMC concentrates contained more monocytes (31.4 ± 12.4% vs 18.5 ± 13.7%; P = 0.019). Among the first 28 CD19-CAR T-cell products manufactured, four had poor expansion yielding less than 1 × 106 transduced T cells per kilogram. When PBMC concentrates from these four patients were compared with the 24 others, PBMC concentrates of poorly expanding products contained greater quantities of monocytes (39.8 ± 12.9% vs. 15.3 ± 10.8%, P = 0.0014). Among the patients whose CD19-CAR T cells expanded poorly, manufacturing for two patients was repeated using cryopreserved PBMC concentrates but incorporating a monocyte depleting plastic adherence step, and an adequate dose of CAR T cells was produced for both patients. Conclusions Variability in CAR T-cell expansion is due, at least in part, to the contamination of the starting PBMC concentrates with monocytes. [ABSTRACT FROM AUTHOR]

The article reports on a randomized, placebo-controlled trial to investigate the effects of recombinant, placebo-controlled trial to investigate the effects of recombinant human growth hormone protein. Induction therapy results found that after 12 weeks, the patients sustained losses in their visceral adipose tissues and trunk fat, but not of subcutaneous fat. It is reported that the therapy also has beneficial effects on the lipid profile.