Revisiting the Sham: Is It all Smoke and Mirrors?

The misuse of sham controls in examining the efficacy or effectiveness of Complementary and Alternative Medicine has created numerous problems. The theoretical justification for incorporating a sham is questionable. The sham does not improve our control of bias and leads to relativistic data that, in most instances, has no appropriate interpretation with regards to treatment efficacy. Even the concept of a sham or placebo control in an efficacy trial is inherently paradoxical. Therefore, it is prudent to re-examine how we view sham controls in the context of medical research. Extreme caution should be used in giving weight to any sham-controlled study claiming to establish efficacy or safety

Tuning the bandgap of Cs2AgBiBr6 through dilute tin alloying.

The promise of lead halide hybrid perovskites for optoelectronic applications makes finding less-toxic alternatives a priority. The double perovskite Cs2AgBiBr6 (1) represents one such alternative, offering long carrier lifetimes and greater stability under ambient conditions. However, the large and indirect 1.95 eV bandgap hinders its potential as a solar absorber. Here we report that alloying crystals of 1 with up to 1 atom% Sn results in a bandgap reduction of up to ca. 0.5 eV while maintaining low toxicity. Crystals can be alloyed with up to 1 atom% Sn and the predominant substitution pathway appears to be a ∼2 : 1 substitution of Sn2+ and Sn4+ for Ag+ and Bi3+, respectively, with Ag+ vacancies providing charge compensation. Spincoated films of 1 accommodate a higher Sn loading, up to 4 atom% Sn, where we see mostly Sn2+ substitution for both Ag+ and Bi3+. Density functional theory (DFT) calculations ascribe the bandgap redshift to the introduction of Sn impurity bands below the conduction band minimum of the host lattice. Using optical absorption spectroscopy, photothermal deflection spectroscopy, X-ray absorption spectroscopy, 119Sn NMR, redox titration, single-crystal and powder X-ray diffraction, multiple elemental analysis and imaging techniques, and DFT calculations, we provide a detailed analysis of the Sn content and oxidation state, dominant substitution sites, and charge-compensating defects in Sn-alloyed Cs2AgBiBr6 (1:Sn) crystals and films. An understanding of heterovalent alloying in halide double perovskites opens the door to a wider breadth of potential alloying agents for manipulating their band structures in a predictable manner

Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer

Lung cancer is the leading cause of cancer deaths, because ~84% of cases are diagnosed at an advanced stage. Worldwide in 2008, ~1.5 million people were diagnosed and ~1.3 million died – a survival rate unchanged since 1960. However, patients diagnosed at an early stage and have surgery experience an 86% overall 5-year survival. New diagnostics are therefore needed to identify lung cancer at this stage. Here we present the first large scale clinical use of aptamers to discover blood protein biomarkers in disease with our breakthrough proteomic technology. This multi-center case-control study was conducted in archived samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. We measured >800 proteins in 15uL of serum, identified 44 candidate biomarkers, and developed a 12-protein panel that distinguished NSCLC from controls with 91% sensitivity and 84% specificity in a training set and 89% sensitivity and 83% specificity in a blinded, independent verification set. Performance was similar for early and late stage NSCLC. This is a significant advance in proteomics in an area of high clinical need

Children and Their Parents’ Assessment of Postoperative Surgical Pain: Agree or Disagree?

Objective The purpose of this study is to compare postoperative pain scores between children undergoing tonsillectomy and adenoidectomy (T&A) surgery and their parents, identify potential predictors for this disagreement, and determine possible impact on analgesic administration. Methods This is a prospective longitudinal study conducted with children undergoing outpatient T&A in 4 major tertiary hospitals and their parents. Children and their parents were enrolled prior to surgery and completed baseline psychological instruments assessing parental anxiety (STAI), parental coping style (MBSS), child temperament (EAS) and parental medication administration attitude questionnaire (MAQ). Postoperatively, parents and children completed at-home pain severity ratings (Faces Pain Scale-Revised, children; Numeric Rating Scale, parents) on postoperative recovery days 1, 2, and 3, reflecting an overall pain level for the past 24 h. Parents also completed a log of analgesic administration. Based on postoperative pain scores, parent-child dyads were classified as overestimators (i.e., parents rated their child\u27s pain higher than children rated their own pain), in agreement (i.e., rating in agreement), or underestimators (i.e., parents rated their child\u27s pain lower than children rated their own pain). Results A significant proportion of parent-child pairs disagreed on pain ratings on postoperative days 1–3 (30.05%–35.95%). Of those pairs in disagreement, the majority of parents overestimated their child\u27s pain on all three postoperative days, specifically such that a total of 24–26% parents overestimated their child\u27s pain on postoperative days 1, 2, and 3. Repeated measures ANOVA demonstrated that parents in the overestimator group administered higher, though still within safe limits, amounts of ibuprofen and oxycodone (mg/day) than did the underestimator or agreement groups. Multiple regression models showed hospital site as the only independent predictor for postoperative pain rating disagreement between children and parents. Conclusions Since parents overestimate their child\u27s postoperative pain and may administer more analgesics to their child, it is essential to develop a standardized method of child pain assessment and a tailored recommended postoperative analgesic regimen amongst medical providers for children undergoing T&A

Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulin-dependent process.

G protein-Coupled Receptors (GPCRs) kinases (GRKs) play a crucial role in regulating cardiac hypertrophy. Recent data from our lab has shown that, following ventricular pressure overload, GRK5, a primary cardiac GRK, facilitates maladaptive myocyte growth via novel nuclear localization. In the nucleus, GRK5\u27s newly discovered kinase activity on histone deacetylase 5 induces hypertrophic gene transcription. The mechanisms governing the nuclear targeting of GRK5 are unknown. We report here that GRK5 nuclear accumulation is dependent on Ca(2+)/calmodulin (CaM) binding to a specific site within the amino terminus of GRK5 and this interaction occurs after selective activation of hypertrophic Gq-coupled receptors. Stimulation of myocytes with phenylephrine or angiotensinII causes GRK5 to leave the sarcolemmal membrane and accumulate in the nucleus, while the endothelin-1 does not cause nuclear GRK5 localization. A mutation within the amino-terminus of GRK5 negating CaM binding attenuates GRK5 movement from the sarcolemma to the nucleus and, importantly, overexpression of this mutant does not facilitate cardiac hypertrophy and related gene transcription in vitro and in vivo. Our data reveal that CaM binding to GRK5 is a physiologically relevant event that is absolutely required for nuclear GRK5 localization downstream of hypertrophic stimuli, thus facilitating GRK5-dependent regulation of maladaptive hypertrophy

A Comprehensive Examination of the Immediate Recovery of Children Following Tonsillectomy and Adenoidectomy

Objectives Using multiple well-validated measures and a large sample size, the goal of this paper was to describe the immediate clinical and behavioral recovery of children following tonsillectomy with or without an adenoidectomy (T&A) during the first two weeks following surgery. Study design Observational, longitudinal study. Setting Four major pediatric hospitals in the U.S. consisting of Children\u27s Hospital of Orange County, Children\u27s Hospital of Los Angeles, Lucile Packard Children\u27s Hospital, and Children\u27s Hospital Colorado. Subjects and Methods: Participants included 827 patients between 2 and 15 years of age who underwent tonsillectomy with or without adenoidectomy surgery. Baseline and demographic information were gathered prior to surgery, and measures of clinical, behavioral, and physical recovery were recorded immediately following and up through two weeks after surgery. Results Pain following T&A was clinically significant through the first post-operative week and nearly resolved by the end of the second week. Negative behavioral changes were highly prevalent after surgery (75.6% of children at Day 0) through the first week (63.9% at Week 1), and over 20% of children continued to evidence new onset negative behavioral changes at two weeks post-operatively. Children were rated as experiencing significant functional impairment in the immediate three days following surgery and most children returned to baseline functioning by the end of the second week. Conclusions Results of this study suggest that children show immediate impairment in functioning and experience clinically significant pain throughout the first week following T&A, and new onset maladaptive behavioral changes persisting even up to the two-week assessment period

Parental Satisfaction of Child\u27s Perioperative Care

Background Satisfaction in the hospital setting is an important component of both hospital funding and patient experience. When it comes to a child\u27s hospital experience, parent satisfaction of their child\u27s perioperative care is also necessary to understand. However, little research has been conducted on the predictors of this outcome. Therefore, the purpose of this current study was to validate a priori selected predictors for parental satisfaction in their child\u27s perioperative process. Methods Eight hundred and ten pediatric patients who underwent tonsillectomy and adenoidectomy surgery and their parents were included in this study. The primary outcome was assessed using a 21‐item parent satisfaction questionnaire resulting in three satisfaction scores: overall care satisfaction, OR/induction satisfaction, and total satisfaction. Results Descriptive statistics and correlational analysis found that sedative‐premedication, parental presence at anesthesia induction, child social functioning, parental anxiety, and language were all significant predictors of various components of the satisfaction score. Regression models, however, revealed that only parent anxiety and child social functioning remained significant predictors such that parents who reported lower state anxiety (OR/induction satisfaction: OR = 0.975, 95% CI [0.957, 0.994]; total satisfaction: OR = 0.968, 95% CI [0.943, 0.993]) and who had higher socially functioning children (overall care satisfaction: OR = 1.019, 95% CI [1.005, 1.033]; OR/induction satisfaction: OR = 1.011, 95% CI [1.000, 1.022]) were significantly more satisfied with the perioperative care they received. Conclusion Lower parent anxiety and higher child social functioning were predictive of higher parental satisfaction scores

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.MethodsTwenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.Methods26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps