The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy - a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden.

BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

Massage for neck pain.

BACKGROUND: Massage is widely used for neck pain, but its effectiveness remains unclear. OBJECTIVES: To assess the benefits and harms of massage compared to placebo or sham, no treatment or exercise as an adjuvant to the same co-intervention for acute to chronic persisting neck pain in adults with or without radiculopathy, including whiplash-associated disorders and cervicogenic headache. SEARCH METHODS: We searched multiple databases (CENTRAL, MEDLINE, EMBASE, CINAHL, Index to Chiropractic Literature, trial registries) to 1 October 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any type of massage with sham or placebo, no treatment or wait-list, or massage as an adjuvant treatment, in adults with acute, subacute or chronic neck pain. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. We transformed outcomes to standardise the direction of the effect (a smaller score is better). We used a partially contextualised approach relative to identified thresholds to report the effect size as slight-small, moderate or large-substantive. MAIN RESULTS: We included 33 studies (1994 participants analysed). Selection (82%) and detection bias (94%) were common; multiple trials had unclear allocation concealment, utilised a placebo that may not be credible and did not test whether blinding to the placebo was effective. Massage was compared with placebo (n = 10) or no treatment (n = 8), or assessed as an adjuvant to the same co-treatment (n = 15). The trials studied adults aged 18 to 70 years, 70% female, with mean pain severity of 51.8 (standard deviation (SD) 14.1) on a visual analogue scale (0 to 100). Neck pain was subacute-chronic and classified as non-specific neck pain (85%, including n = 1 whiplash), radiculopathy (6%) or cervicogenic headache (9%). Trials were conducted in outpatient settings in Asia (n = 11), America (n = 5), Africa (n = 1), Europe (n = 12) and the Middle East (n = 4). Trials received research funding (15%) from research institutes. We report the main results for the comparison of massage versus placebo. Low-certainty evidence indicates that massage probably results in little to no difference in pain, function-disability and health-related quality of life when compared against a placebo for subacute-chronic neck pain at up to 12 weeks follow-up. It may slightly improve participant-reported treatment success. Subgroup analysis by dose showed a clinically important difference favouring a high dose (≥ 8 sessions over four weeks for ≥ 30 minutes duration). There is very low-certainty evidence for total adverse events. Data on patient satisfaction and serious adverse events were not available. Pain was a mean of 20.55 points with placebo and improved by 3.43 points with massage (95% confidence interval (CI) 8.16 better to 1.29 worse) on a 0 to 100 scale, where a lower score indicates less pain (8 studies, 403 participants; I2 = 39%). We downgraded the evidence to low-certainty due to indirectness; most trials in the placebo comparison used suboptimal massage doses (only single sessions). Selection, performance and detection bias were evident as multiple trials had unclear allocation concealment, utilised a placebo that may not be credible and did not test whether blinding was effective, respectively. Function-disability was a mean of 30.90 points with placebo and improved by 9.69 points with massage (95% CI 17.57 better to 1.81 better) on the Neck Disability Index 0 to 100, where a lower score indicates better function (2 studies, 68 participants; I2 = 0%). We downgraded the evidence to low-certainty due to imprecision (the wide CI represents slight to moderate benefit that does not rule in or rule out a clinically important change) and risk of selection, performance and detection biases. Participant-reported treatment success was a mean of 3.1 points with placebo and improved by 0.80 points with massage (95% CI 1.39 better to 0.21 better) on a Global Improvement 1 to 7 scale, where a lower score indicates very much improved (1 study, 54 participants). We downgraded the evidence to low-certainty due to imprecision (single study with a wide CI that does not rule in or rule out a clinically important change) and risk of performance as well as detection bias. Health-related quality of life was a mean of 43.2 points with placebo and improved by 5.30 points with massage (95% CI 8.24 better to 2.36 better) on the SF-12 (physical) 0 to 100 scale, where 0 indicates the lowest level of health (1 study, 54 participants). We downgraded the evidence once for imprecision (a single small study) and risk of performance and detection bias. We are uncertain whether massage results in increased total adverse events, such as treatment soreness, sweating or low blood pressure (RR 0.99, 95% CI 0.08 to 11.55; 2 studies, 175 participants; I2 = 77%). We downgraded the evidence to very low-certainty due to unexplained inconsistency, risk of performance and detection bias, and imprecision (the CI was extremely wide and the total number of events was very small, i.e < 200 events). AUTHORS' CONCLUSIONS: The contribution of massage to the management of neck pain remains uncertain given the predominance of low-certainty evidence in this field. For subacute and chronic neck pain (closest to 12 weeks follow-up), massage may result in a little or no difference in improving pain, function-disability, health-related quality of life and participant-reported treatment success when compared to a placebo. Inadequate reporting on adverse events precluded analysis. Focused planning for larger, adequately dosed, well-designed trials is needed.

Incidence and Predictors of Nonventilator Hospital-Acquired Pneumonia in a Community Hospital.

BACKGROUND: Nonventilator hospital-acquired pneumonia (NV-HAP) is a common hospital-acquired condition that is amenable to basic nursing care interventions. PURPOSE: The purpose of this study was to determine the incidence of NV-HAP in a California community hospital and to identify the patient and nursing care factors including missed nursing care associated with its development. METHODS: A retrospective study identified possible NV-HAP cases with ICD-10 (International Classification of Diseases, Tenth Revision) codes and then validated cases using Centers for Disease Control and Prevention confirmatory criteria. RESULTS: The incidence of NV-HAP in our hospital was 0.64 cases per 1000 patient-days. Patient factors most strongly associated with NV-HAP were age (each year of increased age was associated with a 4% increased likelihood of developing NV-HAP) (OR = 1.04-1.07) and the presence of underlying disease, which reduced odds of developing NV-HAP by 36% (OR = 0.36; 95% CI, 0.12-0.98). Head-of-bed elevation reduced by 26% the odds of developing NV-HAP (OR = 0.26; 95% CI, 0.07-0.08). CONCLUSIONS: NV-HAP can be predicted and potentially prevented. Paradoxically, the presence of underlying disease was not positively associated with the development of NV-HAP in this study.

Synergistic collagenase expression and cartilage collagenolysis are phosphatidylinositol 3-kinase/Akt signaling-dependent.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has emerged as a major regulator of cellular functions and has been implicated in several pathologies involving remodeling of extracellular matrix (ECM). The end stage of inflammatory joint diseases is characterized by excessive ECM catabolism, and in this study we assess the role of PI3K signaling in the induction of collagenolytic matrix metalloproteinases (MMPs) in human chondrocytes. We used the most potent cytokine stimulus reported to promote cartilage ECM catabolism, namely interleukin-1 (IL-1) in combination with oncostatin M (OSM). Both OSM and IL-6 (in the presence of its soluble receptor), but not IL-1 nor leukemia inhibitory factor, induced Akt phosphorylation in human chondrocytes. Inhibition of PI3K signaling using LY294002 blocked IL-1+OSM-mediated Akt phosphorylation, induction of MMP-1 and MMP-13, and cartilage collagenolysis. To further explore the role of downstream substrates within the PI3K pathway, complementary use of small molecule inhibitors and specific small interfering RNAs demonstrated that the PI3K subunit p110alpha and Akt1 were required for MMP-1 mRNA induction. MMP-13 induction was also reduced by loss of function of these molecules and by a lack of p110delta, 3-phosphoinositide-dependent kinase-1 or Akt3. We therefore propose that the activities of specific elements of the PI3K signaling pathway, including Akt, are necessary for the synergistic induction of MMP-1 and MMP-13 and the cartilage breakdown stimulated by IL-1+OSM. Our data provide new insight into the mechanism of synergy between IL-1 and OSM and highlight new therapeutic targets for inflammatory joint diseases that aim to repress the expression of collagenases.

Genome-wide identification of novel genes involved in early Th1 and Th2 cell differentiation.

Th cell subtypes, Th1 and Th2, are involved in the pathogenesis or progression of many immune-mediated diseases, such as type 1 diabetes and asthma, respectively. Defining the molecular networks and factors that direct Th1 and Th2 cell differentiation will help to understand the pathogenic mechanisms causing these diseases. Some of the key factors regulating this differentiation have been identified, however, they alone do not explain the process in detail. To identify novel factors directing the early differentiation, we have studied the transcriptomes of human Th1 and Th2 cells after 2, 6, and 48 h of polarization at the genome scale. Based on our current and previous studies, 288 genes or expressed sequence tags, representing approximately 1-1.5% of the human genome, are regulated in the process during the first 2 days. These transcriptional profiles revealed genes coding for components of certain pathways, such as RAS oncogene family and G protein-coupled receptor signaling, to be differentially regulated during the early Th1 and Th2 cell differentiation. Importantly, numerous novel genes with unknown functions were identified. By using short-hairpin RNA knockdown, we show that a subset of these genes is regulated by IL-4 through STAT6 signaling. Furthermore, we demonstrate that one of the IL-4 regulated genes, NDFIP2, promotes IFN-gamma production by the polarized human Th1 lymphocytes. Among the novel genes identified, there may be many factors that play a crucial role in the regulation of the differentiation process together with the previously known factors and are potential targets for developing therapeutics to modulate Th1 and Th2 responses.

Identification of genes involved in the initiation of human Th1 or Th2 cell commitment.

The differentiation of naïve T helper (Th) cells is induced by TCR activation and IL-12/STAT4 or IL-4/STAT6 signaling pathways, forming Th1 and Th2 cells, respectively. In this study, oligonucleotide arrays were used to identify genes regulated during the initiation of human Th1 and Th2 cell differentiation at 2 and 6 h in presence or absence of immunosuppressive TGF-beta. As a result the immediate targets of IL-12, IL-4 and TGF-beta were identified. The effects of IL-12 at this early stage were minimal and consistent with the known kinetics of IL-12Rbeta2 expression. IL-4, however, was observed to rapidly regulate 63 genes, 26 of which were differentially expressed at both the 2- and 6-h time points. Of these IL-4 regulated genes, one-third have previously been observed to display expression changes in the later phases of the polarization process. Similarly to the key regulators, TBX21 and GATA3, the transcription factors SATB1, TCF7 and BCL6 were differentially regulated at the protein level during early Th1 and Th2 cell polarization. Moreover, the developing Th1 and Th2 cells were demonstrated to be responsive to the immunosuppressive TGF-beta and IL-10. In this study, a panel of novel factors that may be important regulators of the differentiation process was identified.

Controlling chemoselectivity in vinyl and allylic C-X bond activation with palladium catalysis: a pK(a)-based electronic switch.

It has been demonstrated that the same Pd catalyst can be used to effect allylic substitution or vinylic cross-coupling reactions selectively and interchangeably on polyfunctionalized olefin building blocks despite the differences in reaction mechanism. This was achieved by altering the pK(a) of the conjugate acid of the allylic leaving group while keeping the vinyl coupling partner constant. In the case of 2,3-dibromo-1-propene, Pd-catalyzed allylic ionization with malonate nucleophile proceeded selectively and quantitatively in the presence of the Suzuki reaction components necessary for cross-coupling. Conversely, the bromide of 2-bromo-1-(4-ethylphenoxy)-2-propene could be cross-coupled selectively without activation of the allylic phenoxy substituent. In both reactions, the same catalyst could then be used to complete the sequence, which typically involved heating as the trigger to promote the second, more reluctant reaction. Mechanistic considerations as well as synthetic applications demonstrating the value of this interchangeable catalyzed sequence are presented.